Elevated Mast Cell Abundance Is Associated with Enrichment of CCR2+ Cytotoxic T Cells and Favorable Prognosis in Lung Adenocarcinoma.
Cancer research
Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) of patient LUAD samples to comprehensively characterize LUAD-infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ CTL, a specific subcluster of preexhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential cross-talk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD. SIGNIFICANCE:Comprehensive characterization of mast cells in lung adenocarcinoma elucidates their heterogeneity and identifies interplay between mast cells and CCR2+ T cells that is associated with a favorable prognosis.
10.1158/0008-5472.CAN-22-3140
Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.
Hepatology communications
Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.
10.1002/hep4.1770
Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma.
Imada A,Shijubo N,Kojima H,Abe S
The European respiratory journal
Angiogenesis is in part related to mast cells. However, the biological significance of mast cells within lung carcinoma remains unclear. Immunohistochemistry was used to stain for tryptase, CD34 and vascular endothelial growth factor (VEGF) in 85 cases of stage I nonsmall cell lung carcinoma. VEGF was found in 33 of 53 adenocarcinomas and 14 of 32 squamous cell carcinomas. Cases of adenocarcinoma had significantly higher mast cell counts than those of squamous cell carcinoma. In adenocarcinoma, mast cell counts in VEGF-positive tumours were significantly higher than in VEGF-negative tumours, whereas in squamous cell carcinoma they were not. Good correlation was observed between intratumoural mast cell counts and microvessel counts. Double staining showed most intratumoural mast cells expressed VEGF. Importantly, only in lung adenocarcinoma, members in the high mast cell count group had significantly worse prognosis than those in the low mast cell count group. It is concluded that tumour-released vascular endothelial growth factors may be related to mast cell accumulation, intratumoural mast cells may produce vascular endothelial growth factor, and stromal mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma.
Immune microenvironment composition in non-small cell lung cancer and its association with survival.
Clinical & translational immunology
OBJECTIVES:In non-small cell lung cancer (NSCLC), the immune system and possibly its composition affect survival. In this study, the immune infiltrate composition in NSCLC patients was evaluated. METHODS:Gene expression data of tumors from early NSCLC patients were obtained from Gene Expression Omnibus (GEO). With CIBERSORT, 22 immune cell fractions were estimated. RESULTS:The immune infiltrate of 1430 pretreatment NSCLC patients contained mostly plasma cells, macrophages and CD8 T cells. Higher fractions of resting mast and CD4 T-helper cells were associated with longer overall survival (OS) (HR = 0.95, < 0.01; HR = 0.98, = 0.04, respectively) and higher fractions of M2 macrophages and active dendritic cells with shorter survival (HR = 1.02, 0.03; HR = 1.03, 0.05, respectively). Adenocarcinoma patients with survival data ( = 587) showed higher fractions of resting mast and resting CD4 T cells, and lower M0 macrophages than squamous cell carcinoma ( = 254), which were associated with OS (HR = 0.95, 0.04; HR = 0.97, 0.01; HR = 1.03, 0.01, respectively). Fractions of memory B cells, naïve CD4 T cells and neutrophils had different associations with survival depending on the subtype. Smokers had had higher fractions of regulatory T cell, follicular helper T cell, neutrophil and M2 macrophage, which were associated with shorter survival (HR = 1.3, < 0.01; HR = 1.13, 0.02; HR = 1.09, 0.03; HR = 1.04, 0.02, respectively). CONCLUSION:Pretreatment differences in immune cell composition in NSCLC are associated with survival and depend on smoking status and histological subtype. Smokers' immune composition is associated with lower survival.
10.1002/cti2.1142
Comprehensive analysis of the association between tumor-infiltrating immune cells and the prognosis of lung adenocarcinoma.
Journal of cancer research and therapeutics
CONTEXT:Increasing evidence has indicated an association between immune cell infiltration in lung adenocarcinoma (LUAD) and clinical outcomes. AIMS:This study aimed to investigate the effect of 22 tumor-infiltrating immune cells (TIICs) on the prognosis of patients with LUAD. SETTINGS AND DESIGN:This was a case-control study. MATERIALS AND METHODS:The CIBERSORT algorithm calculated the proportion of cases from the Cancer Genome Atlas (TCGA) cohort. Cox regression analysis evaluated the effect of TIICs on the prognosis of LUAD. The immune risk score model was constructed based on a statistical correlation. Multivariate cox regression analysis investigated independent factors. P < 0.05 was considered to be statistically significant. RESULTS:Certain immune cells had differential infiltration between normal tissues and LUAD. Univariate Cox regression analysis revealed that four immune cell types were statistically correlated with LUAD-related survival risk, and an immune risk scoring model was constructed. The results indicated that patients in the high-risk group were associated with poor outcomes. In addition, the multivariate cox analysis revealed that the immune risk scoring model was an independent factor for LUAD prognosis prediction. Ultimately, a nomogram was established to comprehensively predict the survival of LUAD patients. CONCLUSIONS:TIICs played an essential role in the prognosis of LUAD. Furthermore, the immune risk score was a poor predictive factor of LUAD, and the established model was reliable in predicting the prognosis of LUAD.
10.4103/jcrt.JCRT_954_19
Role for High-Affinity IgE Receptor in Prognosis of Lung Adenocarcinoma Patients.
Ly Dalam,Zhu Chang-Qi,Cabanero Michael,Tsao Ming-Sound,Zhang Li
Cancer immunology research
Cancer development and biology is influenced by the host immune system. Emerging data indicate that the context of immune cell infiltrates may contribute to cancer prognosis. However, the types of infiltrating immune cells that are critical for cancer development remain controversial. In attempts to gain insights into the immune networks that regulate and/or predict tumor progression, gene expression analysis was conducted on microarray datasets of resected tumor samples from 128 early-stage non-small cell lung cancer (NSCLC) adenocarcinoma patients. By limiting analysis to immune-related genes, we identified a 9-gene signature using MAximizing R Square Algorithm that selected for the greatest separation between favorable and adverse prognostic patient subgroups. The prognostic value of this 9-gene signature was validated in 10 additional independently published microarray datasets of lung adenocarcinoma [ = 1,097; overall survival hazard ratio (HR), 2.05; 95% confidence interval, 1.64-2.56; < 0.0001] and was found to be an independent prognostic indicator relative to tumor stage (overall survival HR, 2.09, 95% confidence interval, 1.65-2.66; < 0.0001). Network analysis revealed that genes associated with Fcε complex () formed the largest and most significant pathway of the signature. Using immunohistochemistry, we validated that MS4A2, the β subunit of the IgE receptor expressed on mast cells, is a favorable prognostic indicator and show that MS4A2 gene expression is an independent prognostic marker for early-stage lung cancer patient survival. .
10.1158/2326-6066.CIR-16-0392
Differences of the immune cell landscape between normal and tumor tissue in human prostate.
Zhang E,Dai F,Mao Y,He W,Liu F,Ma W,Qiao Y
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
BACKGROUND:Over the past few decades, immunological checkpoint therapy has been an increasingly prominent strategy in the treatment of tumors, including prostate cancer (PC). There are few systematic studies of the phenotypic of tumor-infiltrating immune cells in PC tissues. METHODS:CIBERSORT is an analytical tool for estimating the abundance of member cell types in mixed cell population by gene expression data. Herein, we analyzed different levels of tumor-infiltrating immunity cells in normal tissue compared with PC using CIBERSORT. RESULTS:The results showed that proportion of M1 macrophages and resting mast cells presented significant differences in prostate tumor than these normal tissues. A higher proportion of resting mast cells was associated with a worse outcome and M1 macrophages was associated with a favorable outcome. Moreover, the radiotherapy and targeted molecular therapy can affect the immune infiltration of M1 macrophages and resting mast cells. CONCLUSIONS:Resting mast cells and M1 macrophages has an important role in the prognosis of prostate cancer. Our data provides valuable information about the future treatment of PC.
10.1007/s12094-019-02128-5
Prognostic value of immune cells in the tumor microenvironment of early-stage lung cancer: a meta-analysis.
Tuminello Stephanie,Veluswamy Rajwanth,Lieberman-Cribbin Wil,Gnjatic Sacha,Petralia Francesca,Wang Pei,Flores Raja,Taioli Emanuela
Oncotarget
BACKGROUND:Early-stage non-small cell lung cancer (NSCLC) patients carry significant risk of recurrence post-surgery. In-depth characterization of the immune tumor microenvironment (TME) can have prognostic value. This study aimed to evaluate the association of individual immune cell types in the TME with clinical outcomes in surgically resected, early-stage NSCLC. METHODS:We performed a systematic literature search of the National Library of Medicine database through November 2019, investigating predefined biomarkers (CD3+ T cells, CD4+ T helper cells, CD8+ cytotoxic T cells, CD20+ B cells, CD56+ & CD57+ Natural Killer (NK) cells, CD68+ Tissue Associated Macrophages (TAMS), FoxP3+ T regulatory cells, and Mast Cells (MC)), and their association with survival following PRISMA guidelines. RESULTS:Studies that adjusted for important clinical covariates (such as stage and age) showed that higher levels of CD8+ cytotoxic T cells were associated with improved OS (HR = 0.68; 95% CI, 0.50-0.93) and DFS (HR = 0.60; 95% CI, 0.41-0.87), while increased CD20+ B cells (HR = 0.16; 95% CI, 0.04-0.64) and CD 56/57+ NK cells (HR = 0.50; 95% CI, 0.26-0.95) were associated with improved OS; lung cancers with increased FoxP3+ T regulatory cells (HR = 2.22; 95% CI, 1.47-3.34) had worse OS. CONCLUSIONS:Immune cell components of the TME have prognostic value in early-stage, surgically resected NSCLC, and may reveal which patients are more likely to need additional systemic treatment, including immunotherapy. Clinical covariates need to be considered when evaluating the prognostic value of immune cells in the TME.
10.18632/oncotarget.27392
Digital Inference of Immune Microenvironment Reveals Low-Risk Subtype of Early Lung Adenocarcinoma.
Kurbatov Vadim,Balayev Agshin,Saffarzadeh Areo,Heller Danielle R,Boffa Daniel J,Blasberg Justin D,Lu Jun,Khan Sajid A
The Annals of thoracic surgery
BACKGROUND:Classification of lung adenocarcinoma (LUAD) currently relies on the TNM pathological staging system, which cannot fully account for the variability in postsurgery overall survival (OS). Despite the advances in immunotherapy and increased appreciation of the involvement of cancer immune microenvironment (IME) in cancer progression, the contribution of IME to postsurgery LUAD prognosis is not well understood. METHODS:We digitally inferred the contribution of 22 immune cell types or activation states to the tumor IME using CIBERSORT (Celltype Identification By Estimating Relative Subsets Of RNA Transcripts) analysis in an exploratory metadataset of 581 patients with early-stage LUAD. Patients were arranged based on similarity in IME using k-means clustering. Relationship to postsurgical OS was tested in univariable and multivariable models using Kaplan-Meier analysis and Cox proportional hazards modeling, respectively. To confirm survival relationships, a support vector machine classifier was constructed from a comparison of low-risk and high-risk IME groups. The classifier was applied to a the Cancer Genome Atlas LUAD validation dataset of 394 patients. RESULTS:Patients with an inferred IME enriched in resting mast cells and depleted of macrophages represented a low-clinical-risk group in both exploratory and validation cohorts. CONCLUSIONS:Variability in the digitally inferred composition of the tumor IME contributes to heterogeneity in postsurgical OS. Our data suggest that low inferred macrophage content and inferred resting activation state of intratumor mast cells are associated with improved clinical outcome. Computational inference can be used to define LUAD risk groups and help guide clinical decision making.
10.1016/j.athoracsur.2019.08.050
A 5-Gene Signature Is Closely Related to Tumor Immune Microenvironment and Predicts the Prognosis of Patients with Non-Small Cell Lung Cancer.
BioMed research international
PURPOSE:Establishing prognostic gene signature to predict clinical outcomes and guide individualized adjuvant therapy is necessary. Here, we aim to establish the prognostic efficacy of a gene signature that is closely related to tumor immune microenvironment (TIME). METHODS AND RESULTS:There are 13,035 gene expression profiles from 130 tumor samples of the non-small cell lung cancer (NSCLC) in the data set GSE103584. A 5-gene signature was identified by using univariate survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) to build risk models. Then, we used the CIBERSORT method to quantify the relative levels of different immune cell types in complex gene expression mixtures. It was found that the ratio of dendritic cells (DCs) activated and mast cells (MCs) resting in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant ( < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and < 0.001 and. CONCLUSION:The 5-gene signature is a powerful and independent predictor that could predict the prognosis of NSCLC patients. In addition, our gene signature is correlated with TIME parameters, such as DCs activated and MCs resting. Our findings suggest that the 5-gene signature closely related to TIME could predict the prognosis of NSCLC patients and provide some reference for immunotherapy.
10.1155/2020/2147397
A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer.
Li Jia,Li Xin,Zhang Chenyue,Zhang Chenxing,Wang Haiyong
Oncology reports
Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non‑small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10‑gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low‑risk group was higher than that in the high‑risk group, and the difference was statistically significant (P=0.003, P=0.014 and P=0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low‑risk group was significantly lower than that in the high‑risk group (P=0.05 and P=0.009, respectively). Kaplan‑Meier survival results showed that patients of the high‑risk group had significantly shorter overall survival (OS) than those of the low‑risk group in the training set (P<0.001). Furthermore, Kaplan‑Meier survival showed that patients of the high‑risk group had significantly shorter OS than those of the low‑risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10‑gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10‑gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.
10.3892/or.2020.7464
Identification of immune cells and mRNA associated with prognosis of gastric cancer.
Wang Mingming,Li Zedong,Peng Yu,Fang Jianyu,Fang Tao,Wu Jiajia,Zhou Jun
BMC cancer
BACKGROUND:The clinical success demonstrates the enormous potential of immunotherapy in cancer treatment. METHODS:This article presented research linking gastric cancer to immune cells, based on RNA-seq data of Stomach adenocarcinoma (STAD) and gene expression profile of GSE84437, 24 kinds of tumor-infiltrating immune cells were quantified by single-sample gene set enrichment analysis. RESULTS:Th2 cells, T helper cells, and Mast cells were identified as prognostic immune cells in both TCGA and GEO groups. Then SUPV3L1 and SLC22A17 were identified as hub genes which may affect immune cell infiltration by correlation analysis. Survival analysis further proved that hub genes and prognostic immune cells are associated with the prognosis of gastric cancer. In gastrointestinal tumors, hub genes and prognostic immune cells also found differences in non-tumor and tumor tissues. CONCLUSIONS:We found that three immune cells infiltration are associated with the prognosis of gastric cancer and further identify two hub genes. These two key genes may affect immune cell infiltration, result in the different prognosis of patients.
10.1186/s12885-020-6702-1
Intratumor IL-17-positive mast cells are the major source of the IL-17 that is predictive of survival in gastric cancer patients.
Liu Xiaosun,Jin Hailong,Zhang Geer,Lin Xianke,Chen Chao,Sun Jianyi,Zhang Yu,Zhang Qing,Yu Jiren
PloS one
Interleukin-17 (IL-17) is prevalent in tumor tissue and suppresses effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating IL-17 and its contribution to tumor progression in human gastric cancer remain poorly understood. In this study, we enrolled 112 gastric cancer patients, immunofluorescence was used to evaluate the colocalization of CD3, CD4, CD56, CD20, CD68, and mast cell tryptase (MCT) with IL-17. Immunohistochemistry was used to evaluate the distribution of microvessel density (CD34), CD66b(+), CD68(+), and FoxP3(+) cells in different microanatomical areas. Prognostic value was determined by Kaplan-Meier analysis and a Cox regression model. The results showed that mast cells, but not T cells or macrophages, were the predominant cell type producing IL-17 in gastric cancer. Significant positive correlations were detected between densities of mast cell-derived IL-17 and microvessels, neutrophils, and regulatory T cells (Tregs). Furthermore, we found that the majority of vascular endothelial cells expressing Interleukin-17 receptor (IL-17R). Kaplan-Meier analysis revealed that increasing intratumor infiltrated mast cells and IL-17(+) cells, as well as MCT(+) IL-17(+) cells, were significantly associated with worse overall survival. These findings indicated that mast cells were the major source of IL-17 in gastric cancer, and intratumor IL-17 infiltration may have promoted tumor progression by enhancing angiogenesis in the tumor microenvironment through the axis of IL-17/IL-17R. IL-17-positive mast cells showed a prognostic factor in gastric cancer, indicating that immunotherapy targeting mast cells might be an effective strategy to control intratumor IL-17 infiltration, and consequently reverse immunosuppression in the tumor microenvironment, facilitating cancer immunotherapy.
10.1371/journal.pone.0106834
Does a polarization state exist for mast cells in cancer?
Presta Ivan,Donato Annalidia,Zaffino Paolo,Spadea Maria Francesca,Mancuso Teresa,Malara Natalia,Chiefari Eusebio,Donato Giuseppe
Medical hypotheses
The data of literature are discordant about the role of mast cells in different types of neoplasms. In this paper the authors propose the hypothesis that tumor-associated mast cells may switch to different polarization states, conditioning the immunogenic capacities of the different neoplasms. Anti-inflammatory polarized mast cells should express cytokines such as interleukin-10 (IL-10) and then mast cells number should be inversely related to the intensity of inflammatory infiltrate. On the contrary, when mast cells do not express anti-inflammatory cytokines their number should be directly related to the intensity of the inflammatory infiltrate. In this paper we briefly argue around feasible approaches, based on the retrospective studies of tumor tissue samples from neoplasms considered "immunologically hot" and neoplasms considered "immunologically cold", through immunohistochemistry and immunofluorescence techniques (confocal microscopy). The establishment of the actual existence of a polarization interchange of mast cells, could lead to a new vision in prognostic terms, useful to contrive new approaches in immunotherapy of tumors.
10.1016/j.mehy.2019.109281
Patterns of immune infiltration in lung adenocarcinoma revealed a prognosis-associated microRNA-mast cells network.
Wang Chunlin,Tang Xi,Wang Jiaojian,Xu Yanhua
Human cell
Immune infiltration of tumor microenvironment is an important determinant for immune response and outcomes. To investigate the diversity and clinical relevance of immune infiltration in lung adenocarcinoma (LUAD), we performed a comprehensive analysis using the bulk tumor transcriptomes. The prognosis significance for immune infiltration was systematically evaluated and sufficient immune infiltration was associated with better outcomes. Resting mast cells emerged as the most strongly associated with better overall survival (OS) and disease-free survival (DFS), whereas the activated mast cells were correlated with adverse survival. Immune infiltration-based classification exhibited clinical relevance and provided a close link between cancer cell-intrinsic genetic events and immune landscape. The immune infiltration-miRNA functional network analysis showed that the resting mast cell-associated miRNAs are mainly involved in the enrichment of development, mRNA metabolic process, myeloid cell differentiation, Wnt, calcium modulating, interferon, p53 pathways. Additionally, we found one promoter (miR-30a) and one suppressor (miR-550a) of resting mast cells. Coupling the detailed analyses of the cellular immune infiltration and the implicated modulation role of miRNAs provides novel type of candidates for LUAD immunotherapy.
10.1007/s13577-019-00300-1