The Tumor Immune Profile of Murine Ovarian Cancer Models: An Essential Tool for Ovarian Cancer Immunotherapy Research

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multiple tissues in the reproductive system and metastasizes widely throughout the peritoneal cavity, responses to immunotherapy are likely hindered by heterogeneous tumor microenvironments (TME) containing a variety of immune profiles. To fully characterize and compare syngeneic model systems that may reflect this diversity, we determined the immunogenicity of six ovarian tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition and cytokine profile of ascites, by single-cell RNA sequencing, flow cytometry, and IHC. The selected models reflect the different cellular origins of EOC (ovarian and fallopian tube epithelium) and harbor mutations relevant to human disease, including Tp53 mutation, PTEN suppression, and constitutive KRAS activation. ID8-p53−/− and ID8-C3 tumors were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumors were primarily infiltrated by tumor-associated macrophages and were unique in MHC class I and II expression. MOE-PTEN/KRAS tumors were capable of forming T-cell clusters. This panel of well-defined murine EOC models reflects some of the heterogeneity found in human disease and can serve as a valuable resource for studies that aim to test immunotherapies, explore the mechanisms of immune response to therapy, and guide selection of treatments for patient populations. Significance: This study highlights the main differences in the immunogenicity and immune composition found in six different models of orthotopic ovarian cancer as an essential tool for future preclinical investigations of cancer immunotherapy.