Increased High-Risk Human Papillomavirus Viral Load Is Associated With Immunosuppressed Microenvironment and Predicts a Worse Long-Term Survival in Cervical Cancer Patients.
Cao Meng,Wang Ying,Wang Depu,Duan Yixin,Hong Wei,Zhang Nana,Shah Walayat,Wang Yili,Chen Hongwei
American journal of clinical pathology
OBJECTIVES:To evaluate the correlation between tumor-infiltrating lymphocytes (TILs) and the viral load of high-risk human papillomavirus (HR-HPV) in cervical cancer patients. METHODS:A total of 62 cervical cancer patients were recruited during 1993-1994 and assigned into four groups treated with radiotherapy alone or radiotherapy combined with chemotherapy and/or thermotherapy. Ki67+ tumor cells, CD4+, CD8+, FoxP3+, OX40+ and granzyme B+ TILs were detected by immunohistochemistry. The viral load of HR-HPV in biopsy tissues before therapy was detected by in situ hybridization. RESULTS:The patients with high HPV viral load showed a significantly lower 15-year survival rate and an advanced International Federation of Gynecology and Obstetrics (FIGO) stage and increased recurrence rate. The distribution of Ki67+ tumor cells, FoxP3+ TILs, and CD8+/FoxP3+ ratio was obviously different between low and high HPV viral load groups. A worse clinical outcome was also implicated with increased HPV viral load tested by Cox regression analysis. CONCLUSIONS:Patients with increased HR-HPV viral load tend to be resistant to therapy with decreased immune surveillance in the immune microenvironment. Thus, HR-HPV viral load would influence the local immune microenvironment, and then further affect the survival of cervical cancer patients.
10.1093/ajcp/aqz186
PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential.
Rotman Jossie,den Otter Leontine A S,Bleeker Maaike C G,Samuels Sanne S,Heeren A Marijne,Roemer Margaretha G M,Kenter Gemma G,Zijlmans Henry J M A A,van Trommel Nienke E,de Gruijl Tanja D,Jordanova Ekaterina S
Frontiers in immunology
PD-1/PD-L1 immune checkpoint inhibitors show potential for cervical cancer treatment. However, low response rates suggest that patient selection based on PD-L1 protein expression is not optimal. Here, we evaluated different PD-L1 detection methods and studied transcriptional regulation of PD-L1/PD-L2 expression by The Cancer Genome Atlas (TCGA) mRNAseq analysis. First, we determined the copy number of the PD-L1/PD-L2 locus by fluorescence hybridization (FISH), PD-L1 mRNA expression by RNA hybridization (RNAish), and PD-L1/PD-L2 protein expression by immunohistochemistry (IHC) on tissue microarrays containing a cohort of 60 patients. Additionally, distribution of PD-L1/PD-L2 was visualized based on flow cytometry analysis of single-cell suspensions (n = 10). PD-L1/PD-L2 locus amplification was rare (2%). PD-L1 mRNA expression in tumor cells was detected in 56% of cases, while 41% expressed PD-L1 protein. Discordant scores for PD-L1 protein expression on tumor cells between cores from one patient were observed in 27% of cases. Interestingly, with RNAish, PD-L1 heterogeneity was observed in only 11% of the cases. PD-L2 protein expression was found in 53%. PD-L1 mRNA and protein expression on tumor cells were strongly correlated (p < 0.001). PD-L1 and PD-L2 protein expression showed no correlation on tumor cells (p = 0.837), but a strong correlation on cells in stromal fields (p < 0.001). Co-expression of PD-L1 and PD-L2 on macrophage-like populations was also observed with flow cytometry analysis. Both PD-L1 and PD-L2 TCGA transcript levels strongly correlated in the TCGA data, and both PD-L1 and PD-L2 strongly correlated with interferon gamma (IFNG) expression/transcript levels (p < 0.0001). Importantly, patients with high PD-L1/PD-L2/IFNG transcript levels had a survival advantage over patients with high PD-L1/PD-L2 and low IFNG expression. Based on these findings, we conclude that PD-L1/PD-L2 expression in cervical cancer is mainly associated with interferon induction and not gene amplification, which makes FISH unsuitable as biomarker. The heterogeneous PD-L1 and PD-L2 expression patterns suggest IHC unreliable for patient selection. RNAish, in conjunction with interferon signaling evaluation, seems a promising technique for immune checkpoint detection. These results warrant further investigation into their prognostic and predictive potential.
10.3389/fimmu.2020.596825
Immunoscore system combining CD8 and PD-1/PD-L1: A novel approach that predicts the clinical outcomes for cervical cancer.
The International journal of biological markers
PURPOSE:Immunoscore was established to evaluate the prognosis of cancer patients. However, the feasibility of Immunoscore for the prognosis of cervical cancer remains unknown. To find other prognostic markers that contribute to immunological importance, immune checkpoint inhibitors targeting programmed cell death protein (PD-1), or its ligand, PD-L1, are of enormous interest. Our purpose is to investigate the expression of CD8 and PD-1/PD-L1 and their potential role in Immunoscore, supplementing the tumor/node/metastasis (TNM) classification of cervical cancer. METHODS:Immunoscore was assessed according to the density of PD-1, PD-L1, and CD8 by immunohistochemistry. The association with overall survival and disease-free survival was assessed by the Kaplan-Meier method. To evaluate the effect of Immunoscore, a Cox proportional hazard regression classification was conducted. To compare the prognostic accuracies of Immunoscore and TNM staging, receiver operating characteristic curves were plotted. RESULTS:Patients with PD-L1 and PD-1 in immune cells had poorer overall survival and disease-free survival; however, PD-L1 in tumor cells that infiltrated more CD8 T cells were related to better overall survival and disease-free survival. These immune factors can be independent predictors for prognoses. According to these factors, a new Immunoscore system with priority in predicting prognoses was established. In receiver operating characteristic analysis for predictions of overall survival (the area under curve (AUC) = 0.833 vs. 0.766) and disease-free survival (AUC = 0.861 vs. 0.729), Immunoscore is more accurate than TNM staging. CONCLUSIONS:Thus, this Immunoscore system is an accurate predictive marker, which can be an important supplement to TNM staging for cervical cancer.
10.1177/1724600819888771
Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment.
Lippens Lien,Van Bockstal Mieke,De Jaeghere Emiel A,Tummers Philippe,Makar Amin,De Geyter Sofie,Van de Vijver Koen,Hendrix An,Vandecasteele Katrien,Denys Hannelore
International journal of cancer
We investigated the potential of tumor-infiltrating immune cells (ICs) as predictive or prognostic biomarkers for cervical cancer patients. In total, 38 patients treated with (chemo)radiotherapy and subsequent surgery were included in the current study. This unique treatment schedule makes it possible to analyze IC markers in pretreatment and posttreatment tissue specimens and their changes during treatment. IC markers for T cells (CD3, CD4, CD8 and FoxP3), macrophages (CD68 and CD163) and B cells (CD20), as well as IL33 and PD-L1, were retrospectively analyzed via immunohistochemistry. Patients were grouped in the low score or high score group based on the amount of positive cells on immunohistochemistry. Correlations to pathological complete response (pCR), cause-specific survival (CSS) and metastasis development during follow-up were evaluated. In analysis of pretreatment biopsies, significantly more pCR was seen for patients with CD8 = CD3, CD8 ≥ CD4, positive IL33 tumor cell (TC) scores, IL33 IC < TC and PD-L1 TC ≥5%. Besides patients with high CD8 scores, also patients with CD8 ≥ CD4, CD163 ≥ CD68 or PD-L1 IC ≥5% had better CSS. In the analysis of posttreatment specimens, less pCR was observed for patients with high CD8 or CD163 scores. Patients with decreasing CD8 or CD163 scores between pretreatment and posttreatment samples showed more pCR, whereas those with increasing CD8 or decreasing IL33 IC scores showed a worse CSS. Meanwhile, patients with an increasing CD3 score or stable/increasing PD-L1 IC score showed more metastasis during follow-up. In this way, the intratumoral IC landscape is a promising tool for prediction of outcome and response to (chemo)radiotherapy.
10.1002/ijc.32893
Clinical significance of peripheral blood and tumor tissue lymphocyte subsets in cervical cancer patients.
Wu Yutuan,Ye Shuang,Goswami Shyamal,Pei Xuan,Xiang Libing,Zhang Xiaoming,Yang Huijuan
BMC cancer
BACKGROUND:Alterations in peripheral blood lymphocytes in cervical cancer have been reported, although conflicting views exist. The present study investigated the distributions of lymphocyte subsets in tumor tissue and peripheral blood samples from cervical cancer patients and precancerous lesion patients, and evaluated the correlations of lymphocyte subsets with clinicopathological and prognostic variables. METHODS:A total of 44 patients with stage IB1-IIA2 cervical cancer and 13 precancerous lesion patients were included. Lymphocytes were collected from the tumor tissue and the peripheral blood, and isolated by Lymphoprep density gradient centrifugation. The percentages of lymphocyte subsets were quantified by flow cytometry analysis, and the differences between lymphocyte subsets in the tumor tissue and peripheral blood were compared by SPSS. In addition, the relationships between lymphocyte subsets and clinicopathological and prognostic variables were analyzed. RESULTS:Our results revealed that the amount of total T lymphocytes, CD8+ T cells, granulocytes, pDCs, CD16+ monocytes and CD56 NK cells were significantly higher in the tumor tissue than in the peripheral blood in the cervical cancer patients, while those of CD4+ T cells, CD4+/CD8+ cell ratio, rdT cells, BDCA1+ mDCs, total monocytes, CD14+ monocytes, NK cells and CD56 NK cells exhibited the opposite trend (p < 0.05). The levels of total pDCs and BDCA1+ mDCs in the peripheral blood were significantly lower in the cervical cancer patients than in the precancerous lesion patients, while the proportion of CD16+ monocytes was elevated (p < 0.05). In addition, some lymphocyte subsets, especially CD4+ cells and CD8+ cells, and the CD4+/CD8+ cell ratio were closely associated with clinicopathological and prognostic parameters. CONCLUSIONS:These results suggested that distinct alterations in infiltrating lymphocyte subsets occurred in the tumor and were associated with clinicopathological and prognostic parameters. Systemic impairment of the immune system may occur in the antitumor response of cervical cancer patients.
10.1186/s12885-020-6633-x
Extracellular vesicles mediated proinflammatory macrophage phenotype induced by radiotherapy in cervical cancer.
Ren Junli,Li Lili,Yu Baofeng,Xu Enwei,Sun Naiping,Li Xiaoning,Xing Zihan,Han Xiaodong,Cui Yaqin,Wang Xiaoyan,Zhang Xiaoxue,Wang Guoliang
BMC cancer
BACKGROUND:Radiotherapy is a highly effective treatment for cervical cancer. Recent studies focused on the radiotherapy induced anti-tumor immunity. Whether tumor-derived extracellular vesicles (EVs) play roles in radiotherapy induced tumor associated macrophage (TAM) polarization remains unclear. MATERIALS AND METHODS:This study analysed the phenotype of macrophages in cancer tissue and peripheral blood of cervical cancer patients using flow cytometry analysis. The role of EVs from plasma of post-irradiated patients on M2-like transformed macrophages was assessed. The M1- and M2-like macrophages were assessed by expression of cell surface markers (CCR7, CD163) and intracellular cytokines (IL-10, TNFα and iNOS). The capacity of phagocytosis was assessed by PD-1 expression and phagocytosis of pHrodo Red E. coli bioparticles. RESULTS:Our results demonstrated that radiotherapy of cervical cancer induced an increase in the number of TAMs and a change in their subtype from the M2-like to the M1-like phenotype (increased expression of CCR7 and decreased expression of CD163). The EVs from plasma of post-irradiated patients facilitated the M2-like to the M1-like phenotype transition (increased expression of CCR7, TNFα and iNOS, and decreased expression of CD163 and IL-10) and increased capacity of phagocytosis (decreased PD-1 expression and increased phagocytosis of pHrodo Red E. coli bioparticles). CONCLUSIONS:Our data demonstrated that irradiation in cervical cancer patients facilitated a proinflammatory macrophage phenotype which could eventually able to mediate anti-tumor immune responses. Our findings highlight the importance of EV in the crosstalk of tumor cells and TAM upon irradiation, which potentially leading to an increased inflammatory response to cancer lesions.
10.1186/s12885-022-09194-z
Construction of an immune-related gene signature for prediction of prognosis in patients with cervical cancer.
Mei Jie,Xing Yan,Lv Jinru,Gu Dingyi,Pan Jiadong,Zhang Yan,Liu Jinhui
International immunopharmacology
Cervical cancer (CeCa) is becoming an intractable public health issue worldwide. Emerging evidence uncovers that the tumor progression and prognosis of patients with CeCa are tightly associated with the abundance of tumor-infiltrating immune cells. In the current study, the abundance of tumor-infiltrating immune cells in CeCa samples was assessed by using the ssGSEA, thereby generating two immune-related groups according to the immune status. A 4-gene prognostic signature (RIPOR2, DAAM2, SORBS1, and CXCL8) was next established based on the grouping and its predictive capability was validated by multiple analyses. The TIMER database was used to evaluate the association between 4 hub gene expression and immune cell infiltration. Immunophenoscore (IPS) was used to assess response to immune checkpoint inhibitors in CeCa samples. As the results, a novel grouping strategy based on immune cell infiltration was developed and validated. Based on the grouping, a 4-gene signature was identified to be an independent prognostic indicator for overall survival (OS) in CeCa patients. Among the 4 hub genes, RIPOR2 and CXCL8 expression were significantly correlated with immune cell infiltration. Besides, higher immune checkpoints expression and IPS scores were found in the 4-gene signature low-risk group, suggesting a more immunoactive status that tended to respond to immune checkpoint inhibitors. To sum up, a novel immune-related signature is established to predict CeCa patients' prognosis and also associated with response to immune checkpoint inhibitors, which might be a promising prognostic stratification strategy and innovate therapeutic management.
10.1016/j.intimp.2020.106882
PD-L1 expression is associated with tumor infiltrating lymphocytes that predict response to NACT in squamous cell cervical cancer.
D'Alessandris Nicoletta,Palaia Innocenza,Pernazza Angelina,Tomao Federica,Di Pinto Anna,Musacchio Lucia,Leopizzi Martina,Di Maio Valeria,Pecorella Irene,Benedetti Panici Pierluigi,Della Rocca Carlo
Virchows Archiv : an international journal of pathology
Cancer immunotherapy has significantly improved the management of many malignancies in recent years. Although cervical cancer is the second most common women's cancer in the world, there are still few information about the role of checkpoint inhibitors in this neoplasm, especially in the neoadjuvant setting. In the present study, we retrieved 38 consecutive patients with squamous cell cervical cancer who underwent platinum-based neoadjuvant chemotherapy (NACT) followed by radical surgery. Pre-therapy biopsies were evaluated for the presence of tumor-infiltrating lymphocytes (TILs), including T (both cytotoxic CD8+ and helper CD4+) and B lymphocytes, macrophages, natural-killer cells, and eosinophils. Immunohistochemistry was performed to characterize the inflammatory cells and to evaluate programmed death-ligand 1 (PD-L1) expression on both neoplastic and inflammatory cells. We divided our study population in three groups using three cut-offs (< 10%, 10-40%, >40%), for both TILs and PD-L1 evaluation. Pathological response to NACT was obtained from the histological reports of the post-therapy surgical specimens. We observed that all cases showed stromal TILs, with a predominance of CD3+/CD4+ T helper cells, thus supporting the strong immunogenic potential of cervical cancer. The vast majority of neoplasms expressed PD-L1: 100% on immune cells and 92% on tumor cells. Firstly, we noticed that the percentage of neoplastic cells PD-L1+ was positively associated with high TIL percentage (p = 0.0073) and with increased PD-L1 expression on inflammatory cells (p = 0.0297). Secondly, we observed a significant correlation between both the percentage (p = 0.0105) of TILs and the expression of PD-L1 (p = 0.01045) on inflammatory cells and pathological response to NACT. These results suggest that cervical cancer could be a good target for immunotherapy, also in the neoadjuvant setting. Furthermore, PD-L1 expression was significantly associated with stromal TILs that interestingly may predict pathological response to NACT.
10.1007/s00428-020-02922-5
Baseline immunity and impact of chemotherapy on immune microenvironment in cervical cancer.
Zhang Yi,Yu Minhua,Jing Ying,Cheng Jiejun,Zhang Caiyan,Cheng Lin,Lu Haijiao,Cai Mei-Chun,Wu Jie,Wang Wenjing,Lou Weihua,Qiu Lihua,Tan Li,Lu Huaiwu,Yin Xia,Zhuang Guanglei,Di Wen
British journal of cancer
BACKGROUND:We aimed to comprehensively evaluate the immunologic landscape at baseline and upon chemotherapy in cervical cancer. The information should aid ongoing clinical investigations of checkpoint blockade immunotherapies in this disease setting. METHODS:A series of 109 cervical carcinoma patients was retrospectively assayed before and after neoadjuvant chemotherapy. Tumour-infiltrating immune markers (CD3, CD4, CD8, CD20, CD56, CD68, PD-1, PD-L1) were assessed by immunohistochemistry. RNA sequencing analysis was performed on matched pre- and post-treatment fresh-frozen tissues. RESULTS:At diagnosis, diverse immune cell types including CD20+ B cells, CD3+ T cells, CD56+ natural killer (NK) cells, and CD68+ macrophages were detected in different proportions of cervical carcinoma. Unsupervised hierarchical clustering evidently showed that CD4+ and CD8+ T cell abundance correlated with PD-L1 expression. Based on the immune infiltration patterns, the patients could be stratified into four groups with prognostic relevance, namely, 'immuno-active', 'immuno-medial', 'immuno-NK', and 'immuno-deficient'. Neoadjuvant chemotherapy was associated with increased CD4, CD8, CD20, and CD56 signals, most prominently in good responders. Transcriptomic data corroborated the improved anticancer immunity and identified immunosuppressive CD200 upregulation following chemotherapeutic intervention. CONCLUSIONS:A subset of cervical cancer harbours active immune microenvironment, and chemotherapy treatment may further exert locoregional immunostimulation. Immune checkpoint inhibitors as combination or maintenance therapies warrant future exploration in clinic.
10.1038/s41416-020-01123-w
Activation of FGD5-AS1 Promotes Progression of Cervical Cancer through Regulating BST2 to Inhibit Macrophage M1 Polarization.
Liu Guokun,Du Xuan,Xiao Li,Zeng Qing,Liu QianLing
Journal of immunology research
Accumulating evidence has elucidated the biological function of lncRNAs in various tumors. FGD5 antisense RNA 1 (FGD5-AS1) is identified as a significant tumor regulator in malignancies. Up to now, the detailed function of FGD5-AS1 in cervical cancer and its underlying molecular mechanisms remain uninvestigated. Bone marrow stromal cell antigen 2 (BST2) can play critical roles in immune response, and the roles of BST2 in cervical cancer was explored currently. The level of FGD5-AS1 and BST2 was detected by qRT-PCR in cervical cancer cells. FGD5-AS1 and BST2 expression was significantly upregulated in cervical cancer cells. Then, the decrease of FGD5-AS1 greatly repressed cervical cancer cell growth in vitro. In addition, FGD5-AS1 silencing repressed BST2 expression and suppressed M2 macrophage polarization. Mechanistically, we confirmed that FGD5-AS1 sponged miR-129-5p to reduce its inhibition on BST2. Furthermore, lack of BST2 depressed cervical cancer cell growth, while inducing apoptosis. Loss of BST2 induced M1 macrophage polarization while blocking M2 macrophage polarization. For another, we demonstrated that FGD5-AS1-triggered M2 macrophage polarization was remarkably reversed by miR-129-5p via suppressing BST2. In conclusion, FGD5-AS1 induced M2 macrophage polarization via sponging miR-129-5p and modulating BST2, thus contributing to cervical cancer development. Our findings revealed FGD5-AS1/miR-129-5p/BST2 as a new potential target for cervical cancer.
10.1155/2021/5857214
The immune landscape during the tumorigenesis of cervical cancer.
Wang Yiying,He Mengdi,Zhang Guodong,Cao Kankan,Yang Moran,Zhang Hongwei,Liu Haiou
Cancer medicine
OBJECTIVE:Deciphering the determinants of the intralesional immune reaction in cervical carcinogenesis may be conducive to improving the understanding of the disease and then improve outcomes. METHODS:Public gene-expression data and full clinical annotation were searched in Gene Expression Omnibus in the joint analysis of the array-based four eligible cohorts. The infiltrating estimation was quantified using microenvironment cell populations-counter algorithm and absolute-mode CIBERSORT and verified by flow cytometry analysis. An unsupervised classification on immune genes strongly associated with progression, designated by linear mixed-effects regression. We determined immune response and signaling features of the different developmental stages and immune phenotypes by functional annotation and systematically correlated the expression of immune checkpoints with cell-infiltrating characteristics. RESULTS:We identified the lesion-intrinsic immunosuppression mechanism was triggered at precancerous stages, such as genome instability and mutation, aerobic glycolysis, activation of proto-oncogene pathways and so forth. Predominant innate and adoptive cells were increasing from normalcy to cancer (B cell, total T cell, regulatory T cells [Tregs], monocytes, neutrophils, and M2-like macrophages) together with the decrease of CD4 T cell and CD8 T cell through the development of cervical cancer. Immune escape initiated on the expression of immunosuppressive molecules from high-grade squamous intraepithelial lesions (HSIL) and culminated in squamous cell carcinoma (SCC). Of note, the expression of immune checkpoints was escalated in the immune-hot and immune-warm phenotype largely encompassed by HSIL and SCC under the stress of both activated and suppressive immune responses. CONCLUSIONS:Immune surveillance is unleashing from low-grade squamous intraepithelial lesions onwards and immune-suppression mechanisms are triggered in HSIL. Thorough knowledge of the immune changing pattern during cervical tumorigenesis contributes to finding the potential therapeutic targets to susceptive patients towards immune checkpoints inhibitors.
10.1002/cam4.3833
Expression of immune cell markers and tumor markers in patients with cervical cancer.
Zhang Liming,Zhang Hui,Huang Yuheng,Xi Xiaowei,Sun Yunyan
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
OBJECTIVE:Cervical cancer is one of the most common cancers worldwide, and immune function may impact disease progression. Serum markers may also be associated with diagnosis and progression. The aim of this study was to explore the clinical usefulness of determining the levels of peripheral blood immune cells and serum tumor markers in predicting diagnosis and prognosis of patients with cervical cancer. METHODS:82 patients with cervical cancer (early stage group: IA-IB1 and IIA1; locally advanced group: IB2 and IIA2), 54 patients with cervical intra-epithelial neoplasia (CIN), and 54 healthy women (control group) were recruited. Inclusion criteria were: (1) patients whose cervical lesions were determined based on biopsy; and (2) patients who had not undergone immunotherapy, chemotherapy, or radiotherapy. The exclusion criteria were as follows: (1) patients with a history of other malignant tumors; (2) patients with heart, kidney, and other organ failure; (3) patients with immune diseases; and (4) pregnant or lactating women. The levels of immunocytes and tumor markers were assayed. The relationships among histopathologic factors were analyzed. The correlation between the levels of immunocytes and tumor markers in patients with different degrees of cervical lesions (pre-invasive or cancer) and healthy women was evaluated. RESULTS:The squamous cell carcinoma antigen and carcinoembryonic antigen levels in the control group and the CIN group were significantly lower than those in the cervical cancer groups (p<0.01). The incidence of lymph node metastasis in the early stage and locally advanced groups were 22.9% (11/48) and 46.2% (12/26), respectively, and 58.8% (20/34) and 7.5% (3/37) in the positive and negative lymphovascular invasion groups, respectively (p<0.05). The levels of CD8 and CD8 CD28 T cells in the early stage group were markedly lower than those in the CIN group and the control group (p=0.014, p=0.008, respectively). The ratio of CD4CD25/CD4 in the cervical cancer groups was significantly higher than in the control group (p<0.01). The increased serum squamous cell carcinoma and carcinoembryonic antigen levels and CD4CD25/CD4 ratio were risk factors for cervical cancer by logistic regression analysis (p<0.05). CONCLUSIONS:In patients with cervical cancer, immune function was impaired compared with that in healthy women and patients with CIN, while squamous cell carcinoma and carcinoembryonic antigen levels were increased. Combined detection of the levels of peripheral blood immune cells and serum tumor markers may be helpful for early detection, diagnosis, and prognosis evaluation of patients with cervical cancer.
10.1136/ijgc-2020-001254
An Efficient Prognostic Immune Scoring System For Colorectal Cancer Patients With Peritoneal Metastasis.
Zhao Yamei,Chen Chao,Xu Xiaoming,Ge Xiaoxu,Ding Kefeng,Zheng Shu,Wang Jian,Sun Lifeng
Oncoimmunology
Immunoscore can accurately predict the prognosis of patients with stage I-III colorectal cancer. However, whether it can be used to predict the prognosis of colorectal cancer peritoneal metastases (CRCPM) remains to be validated. We analyzed peritoneal and ovarian metastases in 68 patients with CRCPM. The immunoscore (IS) was based on the infiltration level of CD3+ and CD8+ T cells, whereas the TBM score was derived from the infiltration level of CD3+, CD8+, CD20+ and CD163+ cells to tumor microenvironment (TME). The predictive value of IS and TBM scores for relapse-free survival (RFS) and overall survival (OS) of patients with CRCPM was analyzed using Kaplan Meier curve and Cox multivariate models. Significant difference in the infiltration levels of different immune cell subtypes in primary lesions, peritoneal metastasis and ovarian metastasis were compared using t-test.CRCPM patients with high IS (>1), high TBM1 score (≥2) or high TBM2 score (≥2) had a significantly longer OS (IS: median OS, not reached vs 23 months, = .0078; TBM1: not reached vs 21.5 months, = .013; TBM2: 39.3 months vs 15.2 months, = .001). On the other hand, patients with high IS had a trend of improved RFS (13.4 months vs 11.0 months, = .067). However, TBM1 and TBM2 score has no predictive utility for RFS. Multivariate analysis revealed that IS, TBM1 and TBM2 can accurately predict OS, but not RFS. Finally, the infiltration level of CD3+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophage was significantly higher in peritoneal metastatic tissue and ovarian metastatic tissue, relative to primary tumor tissues.The IS and TBM score of peritoneal metastases could effectively predict OS of patients with CRCPM. Peritoneal metastasis of colorectal cancer decreased the infiltration level of T and B cells.
10.1080/2162402X.2021.1901464
The value of cytokine levels in triage and risk prediction for women with persistent high-risk human papilloma virus infection of the cervix.
Infectious agents and cancer
BACKGROUND:Cervical cancer is a common cancer among women worldwide and is closely related to high-risk human papillomavirus infection (HR-HPV). The immune microenvironment is thought to play an essential role in viral infection and cancer development; however, this relationship remains controversial. Cytokines are an important part of the immune system. Therefore, in this study, we explored changes in cervical cytokine levels of women with persistent HR-HPV infection and determined the value of cytokine detection in assessing cervical lesions. METHODS:We enrolled 146 patients; 117 had long-term high-risk (HR) HPV infection (> 6 months), and 29 were HPV-negative with previous HR-HPV infection. According to histopathological examination, 43 patients were diagnosed with cervicitis; 35, with low-grade squamous intraepithelial lesions (LSILs); and 39, with high-grade squamous intraepithelial lesions (HSILs). Cytokine levels in vaginal fluid were examined using cytometric bead array, and the values of interleukin (IL)-6 and IL-2 levels were converted to a cytokine score. The performance of the cytokine score for diagnosis and risk assessment was compared with that of ThinPrep cytology tests (TCTs). RESULTS:Disease severity was positively associated with IL-6 levels and inversely related to IL-2 levels. The area under the curve (AUC) was higher for the cytokine score including IL-6 and IL-2 than for TCTs for HSILs. Comparisons of the sensitivity, specificity, Youden index, and positive and negative predictive values for HSILs demonstrated that the cytokine score was better than TCT. HPV-positive patients with high cytokine scores showed increased risk of developing HSIL within 3 years. The hazard ratio for the cytokine score was 3.12; thus, the risk of developing HSIL was related to the cytokine score. CONCLUSIONS:The cytokine score increased with the severity of cervical lesions and could distinguish more patients from HPV-positive women and predict the risk of disease progression.
10.1186/s13027-019-0231-z
Classification of high-grade cervical intraepithelial neoplasia by p16 , Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management.
Vink Frederique J,Dick Stèfanie,Heideman Daniëlle A M,De Strooper Lise M A,Steenbergen Renske D M,Lissenberg-Witte Birgit I, ,Floore Arno,Bonde Jesper H,Oštrbenk Valenčak Anja,Poljak Mario,Petry Karl U,Hillemanns Peter,van Trommel Nienke E,Berkhof Johannes,Bleeker Maaike C G,Meijer Chris J L M
International journal of cancer
High-grade cervical intraepithelial neoplasia (CIN2 and CIN3) represents a heterogeneous disease with varying cancer progression risks. Biomarkers indicative for a productive human papillomavirus (HPV) infection (HPV E4) and a transforming HPV infection (p16 , Ki-67 and host-cell DNA methylation) could provide guidance for clinical management in women with high-grade CIN. This study evaluates the cumulative score of immunohistochemical expression of p16 (Scores 0-3) and Ki-67 (Scores 0-3), referred to as the "immunoscore" (IS), in 262 CIN2 and 235 CIN3 lesions derived from five European cohorts in relation to immunohistochemical HPV E4 expression and FAM19A4/miR124-2 methylation in the corresponding cervical scrape. The immunoscore classification resulted in 30 lesions within IS group 0-2 (6.0%), 151 lesions within IS group 3-4 (30.4%) and 316 lesions within IS group 5-6 (63.6%). E4 expression decreased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (P < .001). Methylation positivity increased significantly from CIN2 to CIN3 (P < .001) and with increasing immunoscore group (P < .001). E4 expression was present in 9.8% of CIN3 (23/235) and in 12.0% of IS group 5-6 (38/316). Notably, in a minority (43/497, 8.7%) of high-grade lesions, characteristics of both transforming HPV infection (DNA hypermethylation) and productive HPV infection (E4 expression) were found simultaneously. Next, we stratified all high-grade CIN lesions, based on the presumed cancer progression risk of the biomarkers used, into biomarker profiles. These biomarker profiles, including immunoscore and methylation status, could help the clinician in the decision for immediate treatment or a "wait and see" policy to reduce overtreatment of high-grade CIN lesions.
10.1002/ijc.33566
Development of a Novel Immune Infiltration-Based Gene Signature to Predict Prognosis and Immunotherapy Response of Patients With Cervical Cancer.
Yu Sihui,Li Xi,Zhang Jiawen,Wu Sufang
Frontiers in immunology
Predictive models could indicate the clinical outcome of patients with carcinoma. Cervical cancer is one of the most frequently diagnosed female malignancies. Herein, we proposed an immune infiltration-related gene signature that predicts prognosis of patients with cervical cancer and depicts the immune landscape as well. We utilized the transcriptome data of The Cancer Genome Atlas (TCGA) and estimated the infiltration level of 28 immune cell types. We screened out four immune cell types conducive to patient survival and recognized their shared differentially expressed genes (DEGs). Four core genes (CHIT1, GTSF1L, PLA2G2D, and GNG8) that composed the ultimate signature were identified univariate and multivariate Cox regression. The optimal model we built up could distinguish patients with cervical cancer into high-score and low-score subgroups. These two subgroups showed disparity in aspects of patient survival, immune infiltration landscape, and response to immune checkpoint inhibitors. Additionally, we found that GTSF1L was decreased gradually along with the severity of cervical lesions, and its potential role in immune contexture and clinical practice were also demonstrated. Our results suggested that the Immunoscore based on four immune-related genes could serve as a supplementary criterion to effectively foresee the survival outcome, tumor infiltration status, and immunotherapy efficacy of cervical cancer patients.
10.3389/fimmu.2021.709493
Immunotherapy and Systemic Therapy in Metastatic/Recurrent Endometrial and Cervical Cancers.
Lima J,Ali Z,Banerjee S
Clinical oncology (Royal College of Radiologists (Great Britain))
Despite advances in the treatment of gynaecological malignancies, both recurrent endometrial and cervical cancers when not amenable to localised therapy (surgery or radiotherapy), remain incurable with limited prognosis and effective treatment options. Chemotherapy remains the standard of care for women with metastatic endometrial or cervical cancers. The addition of bevacizumab to first-line chemotherapy for metastatic cervical cancer patients represents a significant step forward in improving survival. More recently, immunotherapeutic strategies targeting the PD-1/-L1 pathway have shown clinical activity in both endometrial and cervical cancers. The increased understanding of the molecular biology of these cancers is shaping target-specific treatments. Here we summarise current treatment options and results from clinical trials of immunotherapy and other targeted therapies that have already changed, or have the potential to change, clinical practice in metastatic/recurrent endometrial and cervical cancer.
10.1016/j.clon.2021.07.002
The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives.
Walsh Robert J,Tan David S P
Journal of clinical medicine
Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.
10.3390/jcm10194523
The potential applications of T cell receptor (TCR)-like antibody in cervical cancer immunotherapy.
Human vaccines & immunotherapeutics
Cervical cancer is ranked as the fourth most common cancer in women worldwide. Monoclonal antibody has created a new dimension in the immunotherapy of many diseases, including cervical cancer. The antibody's ability to target various aspects of cervical cancer (oncoviruses, oncoproteins, and signaling pathways) delivers a promising future for efficient immunotherapy. Besides, technologies such as hybridoma and phage display provide a fundamental platform for monoclonal antibody generation and create the opportunity to generate novel antibody classes including, T cell receptor (TCR)-like antibody. In this review, the current immunotherapy strategies for cervical cancer are presented. We have also proposed a novel concept of T cell receptor (TCR)-like antibody and its potential applications for enhancing cervical cancer therapeutics. Finally, the possible challenges in TCR-like antibody application for cervical cancer therapeutics have been addressed, and strategies to overcome the challenges have been highlighted to maximize the therapeutic benefits.
10.1080/21645515.2021.1913960
Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.
Galon Jérôme,Costes Anne,Sanchez-Cabo Fatima,Kirilovsky Amos,Mlecnik Bernhard,Lagorce-Pagès Christine,Tosolini Marie,Camus Matthieu,Berger Anne,Wind Philippe,Zinzindohoué Franck,Bruneval Patrick,Cugnenc Paul-Henri,Trajanoski Zlatko,Fridman Wolf-Herman,Pagès Franck
Science (New York, N.Y.)
The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
10.1126/science.1129139
Cytotoxic CD8 Lymphocytes in the Tumor Microenvironment.
Iwahori Kota
Advances in experimental medicine and biology
In the tumor microenvironment, CD8 T cells play a major role in tumor immunity. CD8 T cells differentiate to cytotoxic T cells, traffic into the tumor microenvironment, and exhibit cytotoxicity against tumor cells. These processes have both positive and negative effects. Enhancements in the cytotoxic activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment are crucial for the development of cancer immunotherapy. To achieve this, several immunotherapies, including cancer vaccines, T cells engineered to express chimeric antigen receptors (CAR T cells), and bispecific T-cell engagers (BiTEs), have been developed. In contrast to cancer vaccines, CAR T cells, and BiTEs, immune checkpoint inhibitors enhance the activity of cytotoxic T cells by inhibiting the negative regulators of T cells.The total number, type, and activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment need to be clarified, particularly for the development of companion diagnostics to identify patients for whom these therapies are effective. Therefore, technologies including TCR repertoire, single-cell, and T-cell cytotoxicity analyses using BiTEs have been developed.Based on these and future innovations, the generation of effective cancer immunotherapies is anticipated.
10.1007/978-3-030-35723-8_4
Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer.
Li Bi-Lan,Wan Xiao-Ping
Journal of cellular and molecular medicine
Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8 T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.
10.1111/jcmm.15408
The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma.
Uryvaev Anton,Passhak Maria,Hershkovits Dov,Sabo Edmond,Bar-Sela Gil
Medical oncology (Northwood, London, England)
Immunotherapy plays an important role in cancer treatment. Biomarkers that can predict response, including tumor-infiltrating lymphocytes (TILs), are in the spotlight of many studies. This cohort study was designed to evaluate the role of CD4+ and CD8+ TILs as predictive factors for response to anti PD-1 treatment in patients with metastatic non-small cell lung cancer (NSCLC) or metastatic melanoma. We evaluated the expression of CD4+ and CD8+ TILs in tissue samples of 56 patients with metastatic NSCLC or melanoma treated with anti-PD1 immunotherapy. The study included 30 patients with melanoma and 26 with NSCLC. An association was found between CD8+/CD4+ TILs ratio and response to anti-PD1 treatment in both cancers. Regarding melanoma patients, ratios of CD8+/CD4+ lower than 2 predicted lack of response to treatment (0%) (p = 0.006), while CD8+/CD4+ ratios higher than 2.7 had an 81.3% response rate (p = 0.0001). In addition, we found that the presence of more than 1900/mm of CD8+ lymphocytes in the melanoma tumor predicted a 90% response to therapy. In the metastatic NSCLC group, tumors with CD8+ lymphocyte count under 886/mm showed low response rates (16.7%, p = 0.046). When the CD8+ lymphocyte count was in the range of 886-1899/mm, the response rate was high (60%, p = 0.017). In CD8+/CD4+ ratios lower than 2, the response rate was low (13.3%), and in ratios higher than 2, response rates ranged between 43 and 50% (p = 0.035). The use of CD8+/CD4+ TILs ratios in tumor biopsies may predict response to anti-PD1 treatment in metastatic melanoma and NSCLC.
10.1007/s12032-018-1080-0
Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8 T Cells in Non-Melanoma Cancers Compared to Melanoma.
Cancers
Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8 and CD4 TILs, and TIL response polyfunctionality were determined. Tumor-specific CD8 and CD4 TIL responses were detected in over half of the patients in vitro, and greater CD8 TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4 TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8 and CD4 tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.
10.3390/cancers12113344
TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.
Chauvin Joe-Marc,Pagliano Ornella,Fourcade Julien,Sun Zhaojun,Wang Hong,Sander Cindy,Kirkwood John M,Chen Tseng-hui Timothy,Maurer Mark,Korman Alan J,Zarour Hassane M
The Journal of clinical investigation
T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on tumor antigen-specific (TA-specific) CD8⁺ T cells and CD8⁺ tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⁺ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⁺ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1⁺TIM-3⁺ TA-specific CD8⁺ T cells. PD-1⁺TIGIT⁺, PD-1⁻TIGIT⁺, and PD-1⁺TIGIT⁻ CD8⁺ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⁺ T cells and CD8⁺ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⁺ T cells and CD8⁺ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antitumor CD8⁺ T cell responses in patients with advanced melanoma.
10.1172/JCI80445
B16 melanoma control by anti-PD-L1 requires CD8+ T cells and NK cells: application of anti-PD-L1 Abs and Trp2 peptide vaccines.
Human vaccines & immunotherapeutics
Anti-programmed death ligand 1 (PD-L1) therapy has been beneficial in treating patients with certain cancers. Here, we tested whether anti-PD-L1 therapy is effective for controlling different types of tumors using animal models of TC-1, MC38 and B16. We found that, despite PD-L1 expression, anti-PD-L1 therapy showed little and some antitumor activity in the TC-1 and MC38 models. However, anti-PD-L1 therapy exhibited a more dramatic antitumor effect in the B16 model. This difference in antitumor responses was likely associated with the CD8 + T cell infiltration status of tumor tissues. In the B16 model, CD8 + T cells and to a lesser degree NK cells were found to be responsible for the antitumor response of anti-PD-L1 therapy, as determined by immune cell subset depletion. In particular, CD8 + T cells from B16-bearing mice produced an IFN-γ in response to B16 cells and citrate phosphate buffer-treated B16 cell peptide elutes but not to an immunodominant class I epitope, Trp2, suggesting that CD8 + T cells that recognize neoantigens were induced in B16 tumor-bearing mice and then reactivated by anti-PD-L1 for tumor control. When B16 tumor-bearing mice were treated with anti-PD-L1 in combination with Trp2 peptide vaccines, they displayed significantly more tumor control than either single therapy. Taken together, these studies show that B16 melanomas are more effectively controlled through reactivation of tumor-infiltrating lymphocytes by anti-PD-L1 therapy. Moreover, combined therapy using anti-PD-L1 and Trp2 peptide vaccines is more beneficial for controlling B16 melanomas through reactivation of neoantigen-specific CD8 + T cells and induction of Trp2-specific CD8 + T cells.
10.1080/21645515.2020.1866951
Quantitative and Spatial Analysis of CD8+/PD-1 Tumor-Infiltrating Lymphocytes as a Predictive Biomarker for Clinical Response of Melanoma In-Transit Metastases to Topical Immunotherapy.
Haywood Sophia,Garioch Jennifer,Ramaiya Arjun,Moncrieff Marc
Annals of surgical oncology
BACKGROUND:Melanoma in-transit metastases (ITMs) are a challenge to treat and associated with systemic disease and poor prognosis. Topical diphencyprone (DPCP), a potent contact sensitizer, is an established treatment for melanoma ITMs. This exploratory study investigated the utility of BRAF mutation status, CD8, PD-1, PD-L1, and TILs distribution as biomarkers for response of ITMs to topical immunotherapy (DPCP). METHODS:The ITM deposits of 40 patients treated with DPCP were subjected to biomarker analysis for BRAF status, CD8 and PD-1 expression on tumor-infiltrating lymphocytes (TILs), and tumor PD-L1 expression. Response to DPCP and overall survival (OS) were compared by biomarker status. RESULTS:After 12 weeks, 10 patients (25%) had a complete response, 12 patients (30%) had a partial response, and 18 patients (45%) had no response. No significant association was found between any individual biomarker and response to DPCP or OS. The BRAF mutation rate was 25% (10/40). All the patients with a complete response had BRAF wild-type tumor. Peritumoral CD8+ T-cells were associated with complete response (P = 0.041). Both CD8+ and PD-1 expressions were highly correlated (P < 0.0001), and the highest levels of PD-1 expression were detected at the peritumoral interface (P = 0.0004). Only two cases were PD-L1-positive, and both had a complete response to DPCP (P = 0.043). CONCLUSION:Patients who have BRAF wild-type tumor are more likely to experience a complete response to DPCP. Peritumoral TILs and PD-1 expressions may predict a better response to DPCP. Expression of PD-L1 may be associated with a complete response to DPCP. A larger prospective study is required.
10.1245/s10434-020-08713-1
CD103 Tumor-Resident CD8 T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti-PD-1 Treatment.
Edwards Jarem,Wilmott James S,Madore Jason,Gide Tuba Nur,Quek Camelia,Tasker Annie,Ferguson Angela,Chen Jinbiao,Hewavisenti Rehana,Hersey Peter,Gebhardt Thomas,Weninger Wolfgang,Britton Warwick J,Saw Robyn P M,Thompson John F,Menzies Alexander M,Long Georgina V,Scolyer Richard A,Palendira Umaimainthan
Clinical cancer research : an official journal of the American Association for Cancer Research
Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response. We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy. Increased numbers of CD69CD103 tumor-resident CD8 T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti-PD-1 immunotherapy. Tumor-resident CD8 T-cell numbers are more prognostic than total CD8 T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. .
10.1158/1078-0432.CCR-17-2257
Cervicovaginal microbiota dysbiosis correlates with HPV persistent infection.
Qingqing Bi,Jie Zhu,Songben Qu,Juan Chen,Lei Zhang,Mu Xiaofeng
Microbial pathogenesis
HPV persistent infection is a main event leading to the development of cervical intraepithelial neoplasia and cervical cancer. Earlier to distinguish HPV persistent and transient infection is meaningful but the methods are limited. This study used 16S rDNA sequencing to determine the cervicovaginal microbiota of HPV persistent infection, transient infection and health women. Sequences analysis was performed and according to subsequent statistical analysis, the structure of cervicovaginal microbiota of healthy and transient infection individuals is relatively single, Firmicutes occupy the main composition. However, that of the HPV persistent infection presented a complicated trend and the abundance of Proteobacteria, Actinobacteria, Bacteroidetes and Fusobacteria was higher. The significance p-values of the average species abundance of Firmicutes, Proteobacteria and Bacteroides between HPV persistent and transient infection groups were 0.003, 0.018 and 0.005, respectively. The study also found 36 biomarkers of cervicovaginal microbiota dysbiosis for LDA score>4 among different groups. At genus level, Prevotella, Sphingomonas and Anaerococcus correlated with HPV persistent infection. At species level, Lactobacillus iners correlated with HPV transient infection. Besides, local immune microenvironment was changed with cervicovaginal microbiota dysbiosis. Interleukin-6 and TNF-α were significantly upregulated in cervical secretions from HPV persistent infection compared with those from transient infection and healthy women. Peripheral blood Regulatory T cells and myeloid-derived suppressor cells in patients with HPV persistent infection were also significantly increased. In conclusion, this study identified cervicovaginal microbiota dysbiosis closely related to HPV persistent infection, which provided a new idea and method for the prevention of cervical cancer.
10.1016/j.micpath.2020.104617
PD-L1, Mismatch Repair Protein, and NTRK Immunohistochemical Expression in Cervical Small Cell Neuroendocrine Carcinoma.
Frontiers in oncology
BACKGROUND:Cervical small cell neuroendocrine carcinoma (SCNC) is a rare and aggressive disease that lacks a standard treatment strategy or effective methods of targeted therapy. PD-L1 inhibitors for DNA mismatch repair system-deficient (dMMR) tumors and neurotrophin receptor tyrosine kinase (NTRK) inhibitors offer potential pan-cancer treatments. METHODS:Immunohistochemistry was employed as the main detection method, and any NTRK positive cases, identified by immunohistochemistry, were further submitted for evaluation by fluorescence hybridization (FISH) and real-time polymerase chain reaction (RT-PCR) methods. RESULTS:Forty-six patients were enrolled. Positive PD-L1 expression was seen in 22 of the 43 patients (51.16%) with an average combined positive score of 6.82. PD-L1-positive patients were more likely to have a higher proliferation rate in the tumor, and they experienced less recurrence and death (p = 0.048 and 0.033, respectively) compared with the patients with negative PD-L1 expression. However, in the multivariate analysis, none of the clinical parameters was associated with the expression of PD-L1. There was no association between PD-L1 expression and disease recurrence or overall survival in the Kaplan-Meier analysis. All cases were found to be MMR-stable and lacked NTRK gene fusion. However, pan-Trk expressed in 14 (32.56%) of the 43 tested cases, but FISH and RT-PCR failed to confirm any positive fusion signals in IHC-positive cases. CONCLUSIONS:PD-L1 may be an effective therapeutic target for cervical SCNC. Cervical SCNC is a MMR-stable tumor and lacks NTRK gene fusion. IHC isn't a reliable method in the detection of NTRK gene fusion in cervical SCNC.
10.3389/fonc.2021.752453
Clinicopathologic and genomic characterization of PD-L1-positive uterine cervical carcinoma.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Positive program death-ligand 1 (PD-L1) immunohistochemistry (IHC) is an approved companion diagnostic guiding the use of immune checkpoint inhibitors in uterine cervical carcinoma (CXC). The clinical and genomic features of PD-L1-positive (PD-L1) CXC have not been previously described. We reviewed the clinicopathologic and molecular features of 647 CXC cases that were tested using DAKO 22C3 PD-L1 IHC and comprehensive genomic profiling during the course of clinical care. PD-L1 cases were defined via a combined positive score of ≥ 1. No differences were found in age, genetic ancestry, and HPV status of the PD-L1 (n = 548) and PD-L1 disease subset. The PD-L1 positivity rate varied by histologic subtype of CXC with squamous cell carcinoma (SCC) having a PD-L1 positivity rate of 91% (397/437) and usual-type adenocarcinoma's PD-L1 positivity rate being 60% (35/58). In addition, the PD-L1 positivity rate varied depending on site of the specimen with 89.1% (261/293) positivity rate observed in cervix specimens compared to 25% (2/8) in brain metastases specimens. No significant difference in tumor mutational burden (TMB), microsatellite instability, and CD274 (encoding PD-L1) amplification was observed between PD-L1 and PD-L1 CXC subsets. By combining TMB with PD-L1, an additional 17 patients are eligible for pembrolizumab when compared to PD-L1 testing alone. TERT promoter alterations and APOBEC mutational signature were enriched in the PD-L1 CXC SCC (p = 0.011, and p = 0.004, respectively). Our study reveals important prevalence data on PD-L1 positivity in CXC non-SCC and suggests that further studies in these histologic subtypes are warranted. In addition, we also provide a key framework to guide both specimen selection and future investigations of predictors of immunotherapy response in cervical cancer patients. Lastly, TERT promoter alterations and APOBEC mutational signature may be a biologically unique subset of PD-L1 CXC SCC.
10.1038/s41379-021-00780-3
Pan-Cancer Analysis of Immune Cell Infiltration Identifies a Prognostic Immune-Cell Characteristic Score (ICCS) in Lung Adenocarcinoma.
Zuo Shuguang,Wei Min,Wang Shiqun,Dong Jie,Wei Jiwu
Frontiers in immunology
The tumor microenvironment (TME) consists of heterogeneous cell populations, including malignant cells and nonmalignant cells that support tumor proliferation, invasion, and metastasis through extensive cross talk. The intra-tumor immune landscape is a critical factor influencing patient survival and response to immunotherapy. Gene expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Immune cell infiltration was determined by single-sample Gene Set Enrichment Analysis (ssGSEA) depending on the integrated immune gene sets from published studies. Univariate analysis was used to determine the prognostic value of the infiltrated immune cells. Least absolute shrinkage and selection operator (LASSO) regression was performed to screen for the most survival-relevant immune cells. An immune-cell characteristic score (ICCS) model was constructed by using multivariate Cox regression analysis. The immune cell infiltration patterns across 32 cancer types were identified, and patients in the high immune cell infiltration cluster had worse overall survival (OS) but better progression-free interval (PFI) compared to the low immune cell infiltration cluster. However, immune cell infiltration showed inconsistent prognostic value depending on the cancer type. High immune cell infiltration (High CI) indicated a worse prognosis in brain lower grade glioma (LGG), glioblastoma multiforme (GBM), and uveal melanoma (UVM), and favorable prognosis in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), sarcoma (SARC), and skin cutaneous melanoma (SKCM). LUAD prognosis was significantly influenced by the infiltration of 13 immune cell types, with high infiltration of all but Type 2 T helper (Th2) cells correlating with a favorable prognosis. The ICCS model based on six most survival-relevant immune cell populations was generated that classified patients into low- and high-ICCS groups with good and poor prognoses, respectively. The multivariate and stratified analyses further revealed that the ICCS was an independent prognostic factor for LUAD. The infiltration of immune cells in 32 cancer types was quantified, and considerable heterogeneity was observed in the prognostic relevance of these cells in different cancer types. An ICCS model was constructed for LUAD with competent prognostic performance, which can further deepen our understanding of the TME of LUAD and can have implications for immunotherapy.
10.3389/fimmu.2020.01218
PD-L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy.
Chinn Zachary,Stoler Mark H,Mills Anne M
Histopathology
AIMS:The immunoregulatory enzyme indoleamine dioxygenase 2,3 (IDO) has been implicated in cervical and vulvar squamous carcinomas (SCC) and may represent a mechanism of resistance to anti-PD-1/anti-PD-L1 therapy. However, the relationship between IDO and PD-L1 has not been well-investigated. METHODS AND RESULTS:Sixty-five cases of cervical and vulvar intraepithelial neoplasia and SCC were assessed for IDO and PD-L1 expression. Overall, tumoral PD-L1 expression was seen in 72% of SCC, while 50% expressed IDO; co-expression was seen in 42%. Using the combined positive score (CPS) threshold of 1 to account for both tumoral and immune staining, 83% of SCC expressed PD-L1, 61% expressed IDO and 53% showed co-expression. Cervical SCCs were significantly more likely than human papillomavirus (HPV)-related vulvar SCCs to express tumoral IDO (75% versus 13%, P < 0.001) and demonstrate an IDO CPS ≥ 1 (88% versus 25%, P < 0.001); no significant differences were seen for PD-L1. Additionally, there were no significant differences in IDO and PD-L1 expression in dVIN-associated versus HPV-associated vulvar SCC. In contrast to SCC, the majority of intraepithelial lesions were entirely negative for tumoral PD-L1 and IDO and had a CPS score of <1. CONCLUSIONS:In summary, IDO and PD-L1 co-expression is common in cervical SCCs and, to a lesser extent, vulvar SCCs. These data suggest a role for combination immunotherapy in a subset of cervical SCCs as well as select vulvar SCCs. Expression for both markers is less common in intraepithelial lesions, providing no strong support for this form of immunotherapy in the absence of invasion.
10.1111/his.13723
Prognostic significance of PD-L1 protein expression and copy number gains in locally advanced cervical cancer.
Asian Pacific journal of allergy and immunology
BACKGROUND:Although immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1) have demonstrated promising results in several solid malignancies, including cervical cancer, there are some limitations to using PD-L1 immunohistochemical expression as a predictive biomarker for selecting patients who may benefit from such therapy. OBJECTIVE:To examine the protein expression and genetic status of PD-L1 with clinical outcomes in locally advanced cer- vical cancer. METHODS:We investigated the PD-L1 gene copy number gains assessed by fluorescence in situ hybridization (FISH) and PD-L1 expression using immunohistochemistry in 123 patients with locally advanced cervical cancers between December 2008 and December 2016. RESULTS:The prevalence of PD-L1 immunohistochemical expression was detected in 103/123(83%) cases. PD-L1 gene am- plification and polysomy were detected in 7% and 40% of cases, respectively. PD-L1 gene amplification and polysomy were associated with positive PD-L1 immunostaining (score 1+ to 3+) in 88% and 68% of cases, respectively. Clinically, PD-L1 immunopositivity was associated with parametrial invasion at diagnosis. In contrast, PD-L1 polysomy was associated with parametrial invasion and FIGO stages III-IV, whereas PD-L1 amplification was associated with nodal metastasis. In multi- variate analysis, PD-L1 amplification was predictive of worse RFS (HR, 5.68; 95%CI, 1.98-16.28; p = 0.001), whereas PD-L1 polysomy was predictive of worse LRR (HR, 4.13; 95%CI, 1.63-10.49; p = 0.003). PD-L1 immunohistochemical expression was not associated with worse outcomes in Cox models. CONCLUSIONS:Our results showed that an increase in PD-L1 gene copy number could be a novel prognostic and possible predictive biomarker for anti-PD-1/PD-L1 therapy in locally advanced cervical cancer.
10.12932/AP-120419-0538
Immune-Inhibitory Gene Expression is Positively Correlated with Overall Immune Activity and Predicts Increased Survival Probability of Cervical and Head and Neck Cancer Patients.
Budhwani Megha,Turrell Gavin,Yu Meihua,Frazer Ian H,Mehdi Ahmed M,Chandra Janin
Frontiers in molecular biosciences
Limited immunotherapy options are approved for the treatment of cervical cancer and only 10-25% of patients respond effectively to checkpoint inhibition monotherapy. To aid the development of novel therapeutic immune targets, we aimed to explore survival-associated immune biomarkers and co-expressed immune networks in cervical cancer. Using The Cancer Genome Atlas (TCGA) Cervical Squamous Cell Carcinoma (CESC) data ( = 304), we performed weighted gene co-expression network analysis (WGCNA), and determined which co-expressed immune-related genes and networks are associated with survival probability in CESC patients under conventional therapy. A "Pan-Immune Score" and "Immune Suppression Score" was generated based on expression of survival-associated co-expressed immune networks and immune suppressive genes, which were subsequently tested for association with survival probablity using the TCGA Head Neck Squamous Cell Carcinoma (HNSCC) data ( = 528), representing a second SCC cancer type. In CESC, WGCNA identified a co-expression module enriched in immune response related genes, including 462 genes where high expression was associated with increased survival probability, and enriched for genes associated with T cell receptor, cytokine and chemokine signaling. However, a high level of expression of 43 of the genes in this module was associated with decreased survival probability but were not enriched in particular pathways. Separately, we identified 20 genes associated with immune suppression including inhibitory immune checkpoint and regulatory T cell-related genes, where high expression was associated with increased survival probability. Expression of these 20 immune suppressive genes (represented as "Immune Suppression Score") was highly correlated with expression of overall survival-associated immune genes (represented as "Pan-Immune Score"). However, high expression of seven immune suppression genes, including TWEAK-R, CD73, IL1 family and TGFb family genes, was significantly associated with decreased survival probability. Both scores also significantly associated with survival probability in HNSCC, and correlated with the previously established "Immunophenoscore." CESC and HNSCC tumors expressing genes predictive of T cell infiltrates (hot tumors) have a better prognosis, despite simultaneous expression of many immune inhibitory genes, than tumors lacking expression of genes associated with T cell infiltrates (cold tumors) whether or not these tumor express immune inhibitory genes.
10.3389/fmolb.2021.622643
Comprehensive analysis of lymph nodes metastasis associated genes in cervical cancer and its significance in treatment and prognosis.
Yang Ping,Ruan Youqin,Yan Zhiling,Gao Yang,Yang Hongying,Wang Shaojia
BMC cancer
BACKGROUND:Cervical carcinoma is one of the most common malignant tumors of the female reproductive system. Lymph nodes metastasis, the most common metastasis, which can be detected even in small-size tumor patients, results in worse prognosis. Therefore, it is of great significance to explore novel lymph nodes metastasis associated biomarkers, which can predict the prognosis and provide a good reference for clinical decision making in cervical carcinoma patients. However, systematic and comprehensive studies related to the key molecules in lymph node metastasis in cervical carcinoma patients are still absent. METHODS:Transcriptome and clinical data of 307 cervical carcinoma patients were obtained from The Cancer Genome Atlas (TCGA). Then, survival of patients with and without lymph node metastasis was analyzed by Kaplan-Meier (K-M) curves. Differential expressed genes (DEGs) were detected between tumor and control samples using limma package and defined as lymph node metastasis related genes. Univariate and multivariate Cox regression analyses were carried out to screen robust prognostic gene signature. The risk score model and nomogram for predicting survival were constructed based on prognostic gene signature. The performance of the risk score model was evaluated by operating characteristic (ROC) curves. Based on risk score, patients were divided into low- and high- risk groups. DEGs, functional enrichment analysis and tumor microenvironment (immune infiltration and expressions of immune checkpoints) were detected in low- and high-risk groups. RESULTS:A total of 103 lymph node metastasis-associated genes were identified. Univariate and multivariate Cox regression analyses identified TEKT2, LPIN2, FABP4 and CXCL2 as prognostic gene signature. The risk score model was constructed and validated in cervical carcinoma patients. 345 DEGs identified between high- and low-risk groups were significantly enriched into immune-related biological processes. Furthermore, we found that the immune infiltration and expressions of immune checkpoints were significantly different between low- and high-risk groups. CONCLUSION:Our study revealed that lymph node metastasis played an important role in the prognosis of cervical carcinoma patients. Furthermore, we established a risk score model based on lymph node metastasis related genes, which could accurately predict the survival of cervical carcinoma patients. Besides, our findings in tumor microenvironments of low- and high-risk groups improved our understanding of the relationship between lymph node metastasis related genes and cervical carcinoma.
10.1186/s12885-021-08945-8
PD-L1 Expression in Endocervical Adenocarcinoma: Correlation With Patterns of Tumor Invasion, CD8+ Tumor-infiltrating Lymphocytes, and Clinical Outcomes.
The American journal of surgical pathology
Programmed death-1 ligand (PD-L1) expression has been used as a predictive marker for response to immune checkpoint inhibitors and has been reported to have prognostic value. Its prevalence and significance in endocervical adenocarcinoma (ECA) remain underinvestigated. We evaluated PD-L1 expression and CD8+ tumor-infiltrating lymphocyte density in whole tissue sections of 89 ECAs. PD-L1 expression was observed in 68% of ECAs by combined positive score (CPS, cutoff 1) and 29% of ECAs by tumor proportion score (TPS, cutoff 1%). Using CPS, PD-L1 expression was seen in 11%, 78%, and 72% of pattern A, B, and C tumors, respectively, with significantly higher expression in tumors with destructive-type invasion (B and C) (P=0.001 [A vs. B], 0.0006 [A vs. C], 0.0002 [A vs. B+C]). Using TPS, no significant difference in PD-L1 expression was seen between tumors with different invasion patterns (0%, 22%, and 32% in tumors with pattern A, B, and C, respectively; P=0.27 [A vs. B], 0.053 [A vs. C], 0.11 [A vs. B+C]). PD-L1-positive ECAs demonstrated significantly higher CD8+ tumor-infiltrating lymphocyte density (CPS: P=0.028; TPS: P=0.013) and worse progression-free survival when compared with PD-L1-negative ECAs (CPS: hazard ratio [HR]=4.253 vs. 0.235, P=0.025; TPS: HR=4.98 vs. 0.2; P=0.004). When invasion patterns were separately assessed, pattern C tumors similarly showed worse progression-free survival in PD-L1-positive tumors (CPS: HR=6.15 vs. 0.16, P=0.045; TPS: HR=3.78 vs. 0.26, P=0.027). In conclusion, our data show frequent PD-L1 expression in ECA with destructive-type invasion, supporting the role of the PD-1/PD-L1 pathway as a therapeutic target for these tumors. Our data also support PD-L1 as a negative prognostic marker associated with a potentially unfavorable outcome.
10.1097/PAS.0000000000001633
Novel immune-risk score of gastric cancer: A molecular prediction model combining the value of immune-risk status and chemosensitivity.
Duan Shijie,Wang Pengliang,Liu Funan,Huang Hanwei,An Wen,Pan Siwei,Wang Xin
Cancer medicine
Gastric cancer is still one of the most common and deadly malignancies in the world. Not all patients could benefit from chemotherapy or chemoradiotherapy due to tumor heterogeneity. Therefore, identifying different subgroups of patients is an important trend for obtaining more effective responses. However, few molecular classifications associated with chemosensitivity are based on immune-risk status. In this study, we obtained six key immune-related genes. Using these genes, we constructed a molecular model related to immune-risk status and calculated an individual immune-risk score. The score showed great efficiency and stability in predicting prognosis and identifying different subgroups where persons could benefit from postoperative adjuvant therapy. The patients could be divided into different risk groups based on the immune-related score. For patients in the low-risk group, both postoperative chemoradiotherapy and chemotherapy could significantly improve prognosis on overall survival (OS) and disease-free survival (DFS) (DFS, P < 0.001 and P = 0.041, respectively; OS, P < 0.001, P = 0.006, respectively) and chemoradiotherapy was significantly superior than simple chemotherapy (DFS, P = 0.031; OS, P = 0.027). For patients with an intermediate-risk score, postoperative chemoradiotherapy showed a statistically significant survival advantage over no anticancer treatment (P = 0.004 and P = 0.002, respectively), while chemotherapy did not. Compared with no adjuvant treatment, neither postoperative chemoradiotherapy nor chemotherapy made significant difference for patients in the high-risk group. Combining the value of immune-risk status and chemosensitivity, the immune-risk score could not only offer us prognostic evaluation and adjuvant treatment guidance, but also improve our understanding about the binding point between chemotherapy or chemoradiotherapy and the immune system, which may be helpful for further expanding the application of immunotherapy.
10.1002/cam4.2077
Establishment of an Immune Cell Infiltration Score to Help Predict the Prognosis and Chemotherapy Responsiveness of Gastric Cancer Patients.
Jiang Quan,Sun Jie,Chen Hao,Ding Chen,Tang Zhaoqing,Ruan Yuanyuan,Liu Fenglin,Sun Yihong
Frontiers in oncology
The immune microenvironment plays a critical role in tumor biology. The molecular profiles of immune components and related genes are of tremendous value for the study of primary resistance to immune checkpoint blockers (ICBs) for gastric cancer (GC) and serve as prognostic biomarkers to predict GC survival. Recent studies have revealed that tumor immune cell infiltration (ICI) is an indicator of the survival and responsiveness to chemotherapy in GC patients. Here, we describe the immune cell landscape based on the ESTIMATE and CIBERSORT algorithms to help separate GC into 3 ICI clusters using the unsupervised clustering method. Further in-depth analyses, such as differential expression gene (DEG) analysis and principal component analysis (PCA), help to establish an ICI scoring system. A low ICI score is characterized by an increased tumor mutation burden (TMB). The combination of the ICI score and TMB score better predicts the survival of GC patients. Analyses based on public and our own database revealed that the ICI scoring system could also help predict the survival and chemotherapy responsiveness of GC patients. The present study demonstrated that the ICI score may be an effective prognostic biomarker and predictive indicator for chemotherapy and immunotherapy.
10.3389/fonc.2021.650673
Immunogenomic Analyses of Advanced Serous Ovarian Cancer Reveal Immune Score is a Strong Prognostic Factor and an Indicator of Chemosensitivity.
Hao Dapeng,Liu Jie,Chen Meng,Li JingJing,Wang Li,Li Xiaobo,Zhao Qi,Di Li-Jun
Clinical cancer research : an official journal of the American Association for Cancer Research
Ovarian cancer is one of the first human cancers for which immune response was reported to be important for the clinical outcome. To elucidate the mechanistic relationship between immune repertoire and cancer genotype in ovarian cancer, the development of a well-defined immune score for ovarian cancer is required. From a collection of 2,203 patient samples of advanced ovarian cancer from public available resources, we evaluated the prognostic values for a compendium of immune marker genes and proposed an immune score. The relationships between immune score, tumor-infiltrating immune cells, cancer genotypes, and their impact on patient outcome were characterized. Loss of chemokine and IFNγ pathway genes is frequent in ovarian cancer and is significantly associated with low immune score and poor outcome. Chemotherapy can increase the immune score of tumors by inducing the expression of IFNγ inducible chemokines. High immune score is significantly associated with BRCA1/2 mutation status and the response to chemotherapy. Multivariate analysis revealed that immune score is a strong predictor of patient survival and the response to immunotherapy. Our results reveal the drivers of the immune repertoire of advanced ovarian cancer and demonstrate the importance of immune score as an independent prognostic signature and a potent indicator of intratumoral immune status. .
10.1158/1078-0432.CCR-17-3862
Establishment of a Novel Risk Score System of Immune Genes Associated With Prognosis in Esophageal Carcinoma.
Fei Zhenghua,Xie Rongrong,Chen Zhi,Xie Junhui,Gu Yuyang,Zhou Yue,Xu Tongpeng
Frontiers in oncology
Background:Few studies have addressed the role of immune-related genes in the survival and prognosis of different esophageal cancer (EC) sub-types. We established two new prognostic model indexes by bioinformatics analysis to select patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) who may benefit from immunotherapy. Methods:Based on TCGA and ImmPort data sets, we screened immune genes differentially expressed between tumor and normal tissues in ESCC and EAC and analyzed the relationship between these genes and patient survival outcomes. We established the risk score models of immune-related genes in ESCC and EAC by multivariate COX regression analysis. Results:We identified 12 and 11 immune-related differentially expressed genes associated with the clinical prognosis of ESCC and EAC respectively, based on which two prognostic risk score models of the two EC sub-types were constructed. It was found that the survival probability of patients with high scores was significantly lower than that of patients with low scores (p < 0.001). BMP1, EGFR, S100A12, HLA-B, TNFSF18, IL1B, MAPT and OXTR were significantly related to sex, TNM stage or survival outcomes of ESCC or EAC patients (p < 0.05). In addition, the risk score of ESCC was significantly correlated with the level of B cell infiltration in immune cells (p < 0.05). Conclusions:The prognosis-related immune gene model indexes described herein prove to be useful prognostic biomarkers of the two EC sub-types in that they may provide a reference direction for looking for the beneficiaries of immunotherapy for EC patients.
10.3389/fonc.2021.625271
A template to quantify the location and density of CD3 + and CD8 + tumor-infiltrating lymphocytes in colon cancer by digital pathology on whole slides for an objective, standardized immune score assessment.
Lea Dordi,Watson Martin,Skaland Ivar,Hagland Hanne R,Lillesand Melinda,Gudlaugsson Einar,Søreide Kjetil
Cancer immunology, immunotherapy : CII
BACKGROUND:In colon cancer, the location and density of tumor-infiltrating lymphocytes (TILs) can classify patients into low and high-risk groups for prognostication. While a commercially available 'Immunoscore' exists, the incurred expenses and copyrights may prevent universal use. The aim of this study was to develop a robust and objective quantification method of TILs in colon cancer. METHODS:A consecutive, unselected series of specimens from patients with colon cancer were available for immunohistochemistry and assessment of TILs by automated digital pathology. CD3 + and CD8 + cells at the invasive margin and in tumor center were assessed on consecutive sections using automated digital pathology and image analysis software (Visiopharm). An algorithm template for whole slide assessment, generated cell counts per square millimeters (cells/mm), from which the immune score was calculated using distribution volumes. Furthermore, immune score was compared with clinical and histopathological characteristics to confirm its relevance. RESULTS:Based on the quantified TILs numbers by digital image analyses, patients were classified into low (n = 83, 69.7%), intermediate (n = 14, 11.8%) and high (n = 22, 18.5%) immune score groups. High immune score was associated with stage I-II tumors (p = 0.017) and a higher prevalence of microsatellite instable (MSI) tumors (p = 0.030). MSI tumors had a significantly higher numbers of CD3 + TILs in the invasive margin and CD8 + TILs in both tumor center and invasive margin, compared to microsatellite stable (MSS) tumors. CONCLUSION:A digital template to quantify an easy-to-use immune score corresponds with clinicopathological features and MSI in colon cancer.
10.1007/s00262-020-02834-y
A classification based on tumor budding and immune score for patients with hepatocellular carcinoma.
Wei Li,Delin Zhang,Kefei Yuan,Hong Wu,Jiwei Huang,Yange Zhang
Oncoimmunology
: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. : A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. : Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma ( < .001), strong α-SMA expression ( = .005), non-steatotic tumors and non-fibrolamellar-HCC ( < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: IS-TB (type I), IS-TB (type II), IS-TB (type III) and IS-TB (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (ISTB) patients, while IS-TB type IV (ISTB) harbored high number of CTNNB1 mutation. : Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.
10.1080/2162402X.2019.1672495
Stromal-Immune Score-Based Gene Signature: A Prognosis Stratification Tool in Gastric Cancer.
Wang Hao,Wu Xiaosheng,Chen Yiming
Frontiers in oncology
A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the gastric cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to develop a stromal-immune score-based gene signature in gastric cancer. Stromal and immune scores were estimated from transcriptomic profiles of a gastric cancer cohort from TCGA using the ESTIMATE algorithm. A robust partial likelihood-based Cox proportional hazard regression model was applied to select prognostic genes and to construct a stromal-immune score-based gene signature. Two independent datasets from GEO were used for external validation. Favorable overall survivals were found in patients with high stromal score ( = 0.014) and immune score ( = 0.045). Forty-five stromal-immune score-related differentially expressed genes were identified. Using a robust partial likelihood-based Cox proportional hazard regression model, a gene signature containing SOX9, LRRC32, CECR1, and MS4A4A was identified to develop a risk stratification model. Multivariate analysis revealed that the stromal-immune risk score was an independent prognostic factor ( = 0.018). Based on the risk stratification model, the cohort was classified into three groups yielding incremental survival outcomes (log-rank test = 0.0004). A nomogram integrating the risk stratification model and clinicopathologic factors was developed. Calibration and decision curves showed a better performance and net benefits for the nomogram. Similar findings were validated in two independent cohorts. The stromal-immune score-based gene signature represents a prognosis stratification tool in gastric cancer.
10.3389/fonc.2019.01212
A stromal and immune cell infiltration-based score model predicts prognosis and chemotherapy effect in colorectal cancer.
Luo Qingqing,He Feng,Cao Jie
International immunopharmacology
The stromal and immune cells crosstalk with cancer cells in tumor microenvironment, but few studies have fully considered the overall landscape of the infiltrating stromal and immune cells in colorectal cancer. We enrolled 1836 colorectal cancer patients and divided them into the training, validation and test cohorts. 64 stromal and immune cells were quantified in each primary colorectal cancer tissue by estimating gene expression data using xCell algorithm. Univariate, LASSO and multivariate Cox regression analyses were subsequently employed to establish a stromal and immune score prognostic model based on 13 potential cell biomarkers. Patients of the three cohorts were divided into the high- and low-risk groups according to the cutoff value. Compared with the low-risk group, high-risk group showed significant shorter survival, worse clinicopathologic outcomings, higher cancer-related expressions and more active epithelial-mesenchymal transformation. 5-Fu and FUFOL chemotherapy regimens made the low-risk patients gain significant survival advantage, while none chemotherapy regimens benefited the high-risk group, which may benefit from immune checkpoint inhibitors. The nomogram combining the stromal and immune score with standard TNM staging system showed better predictive accuracy than TNM stage alone. The stromal and immune cell infiltration-based score model can effectively and efficiently predict the prognosis and chemotherapy effect in colorectal cancer.
10.1016/j.intimp.2021.107940
Identification and validation of an immune cell infiltrating score predicting survival in patients with lung adenocarcinoma.
Yang Xiaodong,Shi Yu,Li Ming,Lu Tao,Xi Junjie,Lin Zongwu,Jiang Wei,Guo Weigang,Zhan Cheng,Wang Qun
Journal of translational medicine
BACKGROUND:Immune infiltration may predict survival and have clinical significance in lung cancer. However, immune signatures derived from immune profiling based on bulk tumor transcriptomes have not been systematically established in lung adenocarcinoma. We aimed to construct an immune cell infiltrating score, using a new algorithm for evaluating immune infiltration, to improve the prognostic model of lung adenocarcinoma. METHODS:Public datasets of lung adenocarcinoma from the Gene Expression Omnibus and The Cancer Genome Atlas were adopted as the training and validation cohorts. Fractions of different immune cell subtypes in each sample were estimated using the CIBERSORT algorithm. The immune infiltrating score was further developed by a least absolute shrinkage and selection operator regression model. The prognostic value and clinical relationship of the model was then further explored. RESULTS:An immune infiltrating score model was established on the basis of the immune cells in the training cohort. A high score was associated with significantly worse survival in patients with lung adenocarcinoma (P < 0.001). The prognostic value of the score was confirmed in the validation cohort. The immune infiltrating score could improve the accuracy of predictions of survival when combined with the staging system. Furthermore, the score was potentially associated with patient smoking status and histologic subtype of lung adenocarcinoma. Its possible association with the efficacy of adjuvant chemotherapy was not statistically significant. CONCLUSION:The immune cell infiltrating score has prognostic significance in predicting overall survival in patients with lung adenocarcinoma.
10.1186/s12967-019-1964-6
Primary tumor immune score fails to predict the prognosis of colorectal cancer liver metastases after hepatectomy in Chinese populations.
Lin Hao-Cheng,Shao Qiong,Liang Jie-Ying,Wang Yun,Zhang Hui-Zhong,Yuan Yun-Fei,Li Bin-Kui,Wu Xiao-Jun,Chen Gong,Ding Pei-Rong,Lu Zhen-Hai,Pan Zhi-Zhong,Wang De-Shen,Qiu Miao-Zhen,Wang Zhi-Qiang,Wang Feng-Hua,Xu Rui-Hua,Li Yu-Hong
Annals of translational medicine
Background:Increasing evidence suggests that the immune score is significantly associated with cancer prognosis. However, the prognostic role of primary tumor immune score in colorectal cancer liver metastases (CRLM) after hepatectomy in Chinese patients has not been reported. The present study is designed to investigate whether the immune score of primary tumor can predict the postoperative survival of liver metastases in Chinese patients. Methods:A total of 131 patients diagnosed with CRLM were included, and the corresponding primary tumor and liver metastasis specimens were acquired. An immune score ranging from 0 to 4 was established based on the counts and densities of CD3 and CD8 T cells in the core tumor (CT) and the invasive margin (IM). Relapse-free survival (RFS) and overall survival (OS) were analyzed by Kaplan-Meier curves to assess the prognostic role of primary tumor immune score. Furthermore, we conducted a comprehensive search of the Gene Expression Omnibus (GEO) and selected stage IV colorectal cancer (CRC) patients with liver metastasis to compare the tumor-infiltrating T cell profiles of the primary tumor and liver metastases by CIBERSORT. Results:Patients with high immune scores in the primary tumor has no significantly better RFS and OS after hepatectomy than those with low immune scores [median RFS (95% CI): 19.13 (10.07-28.20) . 27.13 (15.97-38.29) months, P=0.604; median OS (95% CI): 64.37 (35.96-92.78) . 40.07 (32.54-47.59) months, P=0.652]. Data collected from the GEO indicates that the proportion of CD8 T cells and total T cells in the primary tumor and liver metastatic lesion are also not significantly correlated (CD8 T cells: r =0.030, P=0.468; total T cells: r =0.165, P=0.076). Conclusions:The immune score of the primary tumor fails to predict the prognosis of CRLM after hepatectomy in Chinese patients.
10.21037/atm-20-4932
Prediction of prognosis of patients with lung cancer in combination with the immune score.
Han Ke,Qian Kun,Zhao Teng,Liu Xing Sheng,Zhang Yi
Bioscience reports
PURPOSE:The host's immune response to malignant tumor is fundamental to tumorigenesis and tumor development. The immune score is currently used to assess prognosis and to guide immunotherapy; however, its association with lung cancer prognosis is not clear. METHODS:Clinical features and immune score data of lung cancer patients from The Cancer Genome Atlas were obtained to build a clinical prognosis nomogram. The model's accuracy was verified by calibration curves. RESULTS:In total, 1005 patients with lung cancer were included. Patients were divided into three groups according to low, medium, and high immune scores. Compared with patients in the low immune score group, the disease-free survival (DFS) of patients in medium and high immune score groups was significantly longer; the hazard ratio (HR) and 95% confidence interval (95% CI) were 0.77 [0.60-0.99] and 0.74 [0.60-0.91], respectively. The overall survival (OS) of patients in the medium and high immune score groups was significantly longer than in the low immune score group; the HR and 95% CI were 0.74 [0.57-0.96] and 0.69 [0.55-0.88], respectively. A clinical prediction model was established to predict the survival prognosis. As verified by calibration curves, the model showed good predictive ability, especially for predicting 3-/5-year DFS and OS. CONCLUSION:Patients with lung cancer with medium and high immune scores had longer DFS and OS than those in low immune score group. Patient prognosis can be effectively predicted by the clinical prediction model combining clinical features and immune score and was consistent with actual clinical outcomes.
10.1042/BSR20203431
The Gustave Roussy Immune (GRIm)-Score Variation Is an Early-on-Treatment Biomarker of Outcome in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with First-Line Pembrolizumab.
Lenci Edoardo,Cantini Luca,Pecci Federica,Cognigni Valeria,Agostinelli Veronica,Mentrasti Giulia,Lupi Alessio,Ranallo Nicoletta,Paoloni Francesco,Rinaldi Silvia,Nicolardi Linda,Caglio Andrea,Aerts Sophie,Cortellini Alessio,Ficorella Corrado,Chiari Rita,Di Maio Massimo,Dingemans Anne-Marie C,Aerts Joachim G J V,Berardi Rossana
Journal of clinical medicine
BACKGROUND:The Gustave Roussy Immune (GRIm)-Score takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic value has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the prognostic and predictive value of baseline GRIm-Score (GRImT0) in advanced non-small cell lung cancer (aNSCLC) patients, we separately investigated two cohorts of patients treated with first-line pembrolizumab or chemotherapy. We also investigated whether GRIm-Score at 45 days since treatment initiation (GRImT1) and GRIm-Score difference between the two timepoints may better predict clinical outcomes (GRImΔ = GRImT0 - GRImT1). METHODS:We retrospectively evaluated 222 aNSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy as the first-line regimen. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-Score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dL. Patients with a GRIm-Score < 2 were considered as having a low Score. RESULTS:In both cohorts, no difference in terms of overall survival (OS) between patients with low and high GRImT0 was found. Otherwise, median OS and progression free survival (PFS) of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, = 0.004; median PFS 10.8 vs. 2.3 months, = 0.002). Patients receiving pembrolizumab with stable/positive GRImΔ had better OS (median OS not reached vs. 12.0 months, < 0.001), PFS (median PFS 20.6 vs. 2.6 months, < 0.001) and objective response rate (58.2% vs. 7.6%, = 0.003) compared to patients with negative GRImΔ. CONCLUSION:Our data shown that GRImT1 and GRImΔ are more reliable peripheral blood biomarkers of outcome compared to GRImT0 in aNSCLC patients treated with pembrolizumab and might represent useful biomarkers to drive clinical decisions in this setting.
10.3390/jcm10051005
Prognostic potential of an immune score based on the density of CD8 T cells, CD20 B cells, and CD33/p-STAT1 double-positive cells and HMGB1 expression within cancer nests in stage IIIA gastric cancer patients.
Dong Jun,Li Jiao,Liu Shiming,Feng Xingyu,Chen Shi,Zhou Zhiwei,Chen Yingbo,Zhang Xiaoshi
Chinese journal of cancer research = Chung-kuo yen cheng yen chiu
OBJECTIVE:There is heterogeneity in the prognosis of gastric cancers staged according to the tumornodes- metastasis (TNM) system. This study evaluated the prognostic potential of an immune score system to supplement the TNM staging system. METHODS:An immunohistochemical analysis was conducted to assess the density of T cells, B cells, and myeloid-derived suppressor cells (MDSCs) in cancer tissues from 100 stage IIIA gastric cancer patients; the expression of the high-mobility group protein B1 (HMGB1) was also evaluated in cancer cells. The relationship between the overall survival (OS), disease-free survival (DFS), and immunological parameters was analyzed. RESULTS:An immune score system was compiled based on the prognostic role of the density of T cells, B cells, MDSCs, and the expression of HMGB1 in cancer tissues. The median 5-year survival of this group of patient was 32%. However, the 5-year survival rates of 80.0%, 51.7%, 0%, 5.8%, and 0% varied among the patients with an immune score of 4 to those with an immune score of 0 based on the immune score system, respectively. Similarly, differences in DFS rates were observed among the immune score subgroups. CONCLUSIONS:An immune score system could effectively identify the prognostic heterogeneity within stage IIIA gastric cancer patients, implying that this immune score system may potentially supplement the TNM staging system, and help in identifying a more homogeneous group of patients who on the basis of prognosis can undergo adjuvant therapy.
10.21147/j.issn.1000-9604.2016.05.10
Mining TCGA Data for Key Biomarkers Related to Immune Microenvironment in Endometrial cancer by Immune Score and Weighted Correlation Network Analysis.
Guo Chengbin,Tang Yuqin,Zhang Yongqiang,Li Gen
Frontiers in molecular biosciences
Endometrial cancer (EC) is one of the most lethal gynecological cancers around the world. The aim of this study is to identify the potential immune microenvironment-related biomarkers associated with the prognosis for EC. RNA-seq data and clinical information of EC patients were derived from The Genome Atlas (TCGA). The immune score of each EC sample was obtained by ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) was used to identify the interesting module and potential key genes concerning the immune score. The expression patterns of the key genes were then verified the GEPIA database. Finally, CIBERSORT was applied to evaluate the relative abundances of 22 immune cell types in EC. Immune scores were significantly associated with tumor grade and histology of EC, and high immune scores may exert a protective influence on the survival outcome for EC. WGCNA indicated that the black module was significantly correlated with the immune score. Function analysis revealed it mainly involved in those terms related to immune regulation and inflammatory response. Moreover, 11 key genes (APOL3, C10orf54, CLEC2B, GIMAP1, GIMAP4, GIMAP6, GIMAP7, GIMAP8, GYPC, IFFO1, TAGAP) were identified from the black module, validated by the GEPIA database, and revealed strong correlations with infiltration levels of multiple immune cell types, as was the prognosis of EC. In this study, 11 key genes showed abnormal expressions and strong correlations with immune infiltration in EC, most of which were significantly associated with the prognosis of EC. These findings made them promising therapeutic targets for the treatment of EC.
10.3389/fmolb.2021.645388