Abstract
BackgroundOvarian cancer (OC) is typically diagnosed late, associated with high rates of metastasis and the onset of ascites during late stage disease. Understanding the tumor microenvironment and how it impacts the efficacy of current treatments, including immunotherapies, needs effective in vivo models that are fully characterized. In particular, understanding the role of immune cells within the tumor and ascitic fluid could provide important insights into why OC fails to respond to immunotherapies. In this work, we comprehensively described the immune cell infiltrates in tumor nodules and the ascitic fluid within an optimized preclinical model of advanced ovarian cancer.MethodsGreen Fluorescent Protein (GFP)‐ID8 OC cells were injected intraperitoneally into C57BL/6 mice and the development of advanced stage OC monitored. Nine weeks after tumor injection, mice were sacrificed and tumor nodules analyzed to identify specific immune infiltrates by immunohistochemistry. Ascites, developed in tumor bearing mice over a 10‐week period, was characterized by mass cytometry (CyTOF) to qualitatively and quantitatively assess the distribution of the immune cell subsets, and their relationship to ascites from ovarian cancer patients.ResultsTumor nodules in the peritoneal cavity proved to be enriched in T cells, antigen presenting cells and macrophages, demonstrating an active immune environment and cell‐mediated immunity. Assessment of the immune landscape in the ascites showed the predominance of CD8+, CD4+, B–, and memory T cells, among others, and the coexistance of different immune cell types within the same tumor microenvironment.ConclusionsWe performed, for the first time, a multiparametric analysis of the ascitic fluid and specifically identify immune cell populations in the peritoneal cavity of mice with advanced OC. Data obtained highlights the impact of CytOF as a diagnostic tool for this malignancy, with the opportunity to concomitantly identify novel targets, and define personalized therapeutic options.
Highlights
Ovarian cancer (OC) is the 7th most common cause of death in women worldwide, with over 21 000 new cases expected in the United States in 2020.1 Survival rates vary according to the stage of disease, with a 5-year survival rate of around 30% for advanced cancers,[2,3] the most common of which is high-grade serous ovarian carcinoma (HGSOC) accounting for more than 50% of cases
Tissue sections were analyzed by immunohistochemistry (IHC) to identify immune cell infiltration within tumors found on the peritoneal membrane
The mouse ovarian surface epithelial cell line (ID8 cell line) is widely used to generate preclinical models of advanced OC. This is due to its capacity to closely reproduce the histopathological nuances that are characteristic of patients with advanced OC
Summary
Ovarian cancer (OC) is the 7th most common cause of death in women worldwide, with over 21 000 new cases expected in the United States in 2020.1 Survival rates vary according to the stage of disease, with a 5-year survival rate of around 30% for advanced cancers,[2,3] the most common of which is high-grade serous ovarian carcinoma (HGSOC) accounting for more than 50% of cases. Liposomal doxorubicin is a viable option for both early and advanced-stage disease.[5] Targeted therapeutic approaches, recently added to standard clinical practice, provide improved survival rates and include: vascular endothelial growth factor (VEGF)-A inhibitors,[6] and poly (ADP-ribose) polymerase (PARP) inhibitors, which are indicated for patients with a BReast CAncer gene (BRCA1/2) mutation.[5] OC remains a complex disease to treat, owing to the high chemotherapy-resistance emergence rate,[7] and in recent years great emphasis has been placed on the employment of immunotherapies to combat this issue, currently no clinically approved immunotherapy for HGSOC exists. We comprehensively described the immune cell infiltrates in tumor nodules and the ascitic fluid within an optimized preclinical model of advanced ovarian cancer. Ascites, developed in tumor bearing mice over a 10-week period, was characterized by mass cytometry (CyTOF) to qualitatively and quantitatively assess the distribution of the immune cell subsets, and their relationship to ascites from ovarian cancer patients. Data obtained highlights the impact of CytOF wileyonlinelibrary.com/journal/ctm[2 1] of 18
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