Nanoadjuvant-Assembled Tumor Vaccine for Preventing Long-Term Recurrence.
Le Quoc-Viet,Suh Juhan,Choi Jin Joo,Park Gyu Thae,Lee Jung Weon,Shim Gayong,Oh Yu-Kyoung
ACS nano
Although immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy, a monotherapy approach is not sufficient. Here, we report an immune checkpoint inhibitor-modified nanoparticle for an -assembled tumor vaccine that can activate immune systems in the tumor microenvironment and prevent the long-term recurrence of tumors. Adjuvant-loaded nanoparticles were prepared by entrapping imiquimod (IQ) in photoresponsive polydopamine nanoparticles (IQ/PNs). The surfaces of IQ/PNs were then modified with anti-PDL1 antibody (PDL1Ab-IQ/PNs) for assembly with inactivated tumor cells and immune checkpoint blocking of PDL1 (programmed cell death 1 ligand 1). The presence of anti-PDL1 antibodies on IQ/PNs increased the binding of nanoparticles to CT26 cancer cells overexpressing PDL1. Subsequent near-infrared (NIR) irradiation induced a greater photothermal anticancer effect against cells treated with PDL1Ab-IQ/PNs than cells treated with plain PNs or unmodified IQ/PNs. To mimic the tumor microenvironment, we cocultured bone marrow-derived dendritic cells with CT26 cells treated with various nanoparticle formulations and NIR irradiated. This coculture study revealed that NIR-inactivated, PDL1Ab-IQ/PN-bound CT26 cells induced maturation of dendritic cells to the greatest extent. Following a single intravenous administration of different nanoparticle formulations in CT26 tumor-bearing mice, PDL1Ab-IQ/PNs showed greater tumor tissue accumulation than unmodified nanoparticles. Subsequent NIR irradiation of mice treated with PDL1Ab-IQ/PNs resulted in tumor ablation. In addition to primary tumor ablation, PDL1Ab-IQ/PNs completely prevented the growth of a secondarily challenged CT26 tumor at a distant site, producing 100% survival for up to 150 days. A long-term protection study revealed that treatment with PDL1Ab-IQ/PNs followed by NIR irradiation inhibited the growth of distant, secondarily challenged CT26 tumors 150 days after the first tumor inoculation. Moreover, increased infiltration of T cells was observed in tumor tissues treated with PDL1Ab-IQ/PNs and NIR-irradiated, and T cells isolated from splenocytes of mice in which tumor recurrence was prevented showed active killing of CT26 cells. These results suggest that PDL1Ab-IQ/PNs in conjunction with NIR irradiation induce a potent, -assembled, all-in-one tumor vaccine with adjuvant-containing nanoparticle-bound, inactivated tumor cells. Such nanoadjuvant-assembled tumor vaccines can be further developed for long-term prevention of tumor recurrence without the need for chemotherapy.
10.1021/acsnano.9b02071
Naturally Killing the Silent Killer: NK Cell-Based Immunotherapy for Ovarian Cancer.
Nersesian Sarah,Glazebrook Haley,Toulany Jay,Grantham Stephanie R,Boudreau Jeanette E
Frontiers in immunology
Ovarian cancer (OC) is diagnosed in ~22,000 women in the US each year and kills 14,000 of them. Often, patients are not diagnosed until the later stages of disease, when treatment options are limited, highlighting the urgent need for new and improved therapies for precise cancer control. An individual's immune function and interaction with tumor cells can be prognostic of the response to cancer treatment. Current emerging therapies for OC include immunotherapies, which use antibodies or drive T cell-mediated cancer recognition and elimination. In OC, these have been limited by adverse side effects and tumor characteristics including inter- and intra-tumoral heterogeneity, lack of targetable antigens, loss of tumor human leukocyte antigen expression, high levels of immunosuppressive factors, and insufficient immune cell trafficking. Natural killer (NK) cells may be ideal as primary or collateral effectors to these nascent immunotherapies. NK cells exhibit multiple functions that combat immune escape and tumor relapse: they kill targets and elicit inflammation through antigen-independent pathways and detect loss of HLA as a signal for activation. NK cells are efficient mediators of tumor immune surveillance and control, suppressed by the tumor microenvironment and rescued by immune checkpoint blockade. NK cells are regulated by a variety of activating and inhibitory receptors and already known to be central effectors across an array of existing therapies. In this article, we highlight interactions between NK cells and OC and their potential to change the immunosuppressive tumor microenvironment and participate in durable immune control of OC.
10.3389/fimmu.2019.01782
Heterogeneity of immune microenvironment in ovarian cancer and its clinical significance: a retrospective study.
Gao Yue,Chen Lingxi,Cai Guangyao,Xiong Xiaoming,Wu Yuan,Ma Ding,Li Shuai Cheng,Gao Qinglei
Oncoimmunology
Treatment of ovarian cancer (OC) remains the biggest challenge among gynecological malignancies. Immune checkpoint blockade therapy is promising in many cancers but shows low response rates in OC because of its heterogeneity. Although the biological and molecular heterogeneity of OC has been extensively investigated, heterogeneity of immune microenvironment remains elusive. We have collected the expression profiles of 3071 OC patients from 22 publicly available datasets. CIBERSORT was applied to infer the infiltration fraction of 22 immune cells among 2086 patients with CIBERSORT < .05. We then explored the heterogeneity landscape of immune microenvironment in OC at three levels (immune infiltration, prognostic relevance of immune infiltration, immune checkpoint expression patterns). Multivariable Cox regression model was used to investigate the associations between survival risk and immune infiltration. Constructed immune risk score stratified patients with significantly different survival risk (HR: 1.47, 95% CI: 1.31-1.66, < .0001). The immune infiltration landscape, prognostic relevance of immune cells, and expression patterns of 79 immune checkpoints exhibited remarkable clinicopathological heterogeneity. For instance, M1 macrophages were significantly associated with better outcomes among patients with high-grade, late-stage, type-II OC (HR: 0.77-0.83), and worse outcomes among patients with type-I OC (HR: 1.78); M2 macrophages were significantly associated with worse outcomes among patients with high-grade, type-II OC (HR: 1.14-1.17); Neutrophils were significantly associated with worse outcomes among patients with high-grade, late-stage, type-I OC (HR: 1.14-1.73). The heterogeneous landscape of immune microenvironment presented in this study provided new insights into prognostic prediction and tailored immunotherapy of OC.
10.1080/2162402X.2020.1760067
Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.
Zhang Allen W,McPherson Andrew,Milne Katy,Kroeger David R,Hamilton Phineas T,Miranda Alex,Funnell Tyler,Little Nicole,de Souza Camila P E,Laan Sonya,LeDoux Stacey,Cochrane Dawn R,Lim Jamie L P,Yang Winnie,Roth Andrew,Smith Maia A,Ho Julie,Tse Kane,Zeng Thomas,Shlafman Inna,Mayo Michael R,Moore Richard,Failmezger Henrik,Heindl Andreas,Wang Yi Kan,Bashashati Ali,Grewal Diljot S,Brown Scott D,Lai Daniel,Wan Adrian N C,Nielsen Cydney B,Huebner Curtis,Tessier-Cloutier Basile,Anglesio Michael S,Bouchard-Côté Alexandre,Yuan Yinyin,Wasserman Wyeth W,Gilks C Blake,Karnezis Anthony N,Aparicio Samuel,McAlpine Jessica N,Huntsman David G,Holt Robert A,Nelson Brad H,Shah Sohrab P
Cell
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
10.1016/j.cell.2018.03.073
Immunotherapy in ovarian cancer.
Annals of oncology : official journal of the European Society for Medical Oncology
Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure.
10.1093/annonc/mdx444
Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.
Färkkilä Anniina,Gulhan Doga C,Casado Julia,Jacobson Connor A,Nguyen Huy,Kochupurakkal Bose,Maliga Zoltan,Yapp Clarence,Chen Yu-An,Schapiro Denis,Zhou Yinghui,Graham Julie R,Dezube Bruce J,Munster Pamela,Santagata Sandro,Garcia Elizabeth,Rodig Scott,Lako Ana,Chowdhury Dipanjan,Shapiro Geoffrey I,Matulonis Ursula A,Park Peter J,Hautaniemi Sampsa,Sorger Peter K,Swisher Elizabeth M,D'Andrea Alan D,Konstantinopoulos Panagiotis A
Nature communications
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
10.1038/s41467-020-15315-8
Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy.
Nature genetics
In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.
10.1038/s41588-020-0630-5
Targeting tumor microenvironment in ovarian cancer: Premise and promise.
Jiang Yuting,Wang Chengdi,Zhou Shengtao
Biochimica et biophysica acta. Reviews on cancer
Ovarian cancer is the leading cause of gynecological cancer-related mortality globally. The majority of ovarian cancer patients suffer from relapse after standard of care therapies and the clinical benefits from cancer therapies are not satisfactory owing to drug resistance. Certain novel drugs targeting the components of tumor microenvironment (TME) have been approved by US Food and Drug Administration in solid cancers. As such, the passion is rekindled to exploit the role of TME in ovarian cancer progression and metastasis for discovery of novel therapeutics for this deadly disease. In the current review, we revisit the recent mechanistic insights into the contributions of TME to the development, progression, prognosis prediction and therapeutic efficacy of ovarian cancer via modulating cancer hallmarks. We also explored potentially promising predictive and prognostic biomarkers for ovarian cancer patients.
10.1016/j.bbcan.2020.188361
Predicting 6- and 12-Month Risk of Mortality in Patients With Platinum-Resistant Advanced-Stage Ovarian Cancer: Prognostic Model to Guide Palliative Care Referrals.
Foote Jonathan,Lopez-Acevedo Micael,Samsa Gregory,Lee Paula S,Kamal Arif H,Alvarez Secord Angeles,Havrilesky Laura J
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
OBJECTIVE:Predictive models are increasingly being used in clinical practice. The aim of the study was to develop a predictive model to identify patients with platinum-resistant ovarian cancer with a prognosis of less than 6 to 12 months who may benefit from immediate referral to hospice care. METHODS:A retrospective chart review identified patients with platinum-resistant epithelial ovarian cancer who were treated at our institution between 2000 and 2011. A predictive model for survival was constructed based on the time from development of platinum resistance to death. Multivariate logistic regression modeling was used to identify significant survival predictors and to develop a predictive model. The following variables were included: time from diagnosis to platinum resistance, initial stage, debulking status, number of relapses, comorbidity score, albumin, hemoglobin, CA-125 levels, liver/lung metastasis, and the presence of a significant clinical event (SCE). An SCE was defined as a malignant bowel obstruction, pleural effusion, or ascites occurring on or before the diagnosis of platinum resistance. RESULTS:One hundred sixty-four patients met inclusion criteria. In the regression analysis, only an SCE and the presence of liver or lung metastasis were associated with poorer short-term survival (P < 0.001). Nine percent of patients with an SCE or liver or lung metastasis survived 6 months or greater and 0% survived 12 months or greater, compared with 85% and 67% of patients without an SCE or liver or lung metastasis, respectively. CONCLUSIONS:Patients with platinum-resistant ovarian cancer who have experienced an SCE or liver or lung metastasis have a high risk of death within 6 months and should be considered for immediate referral to hospice care.
10.1097/IGC.0000000000001182