A TEMPORAL MODEL OF TUMOR-IMMUNE DYNAMICS IN HIGH GRADE SEROUS OVARIAN CANCER

Abstract

Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. We performed multi-site global proteomics and matched immunohistochemistry (IHC) of CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in patient samples. The protein expression profiles were ordered by pseudotime, recapitulating metastatic progression observed in the clinic, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease. Metastatic progression correlated with immune cell infiltration and the recruitment of Tregs to counterbalance the effect of {gamma}{delta} and CD4+ T cells. Whilst later-stage metastases recruited Tregs via chemokines induced by SNX8, early-stage tumors relied more on antigen presentation. The exclusion of CD4+ TILs from the epithelium was correlated with metastatic progression, whereas CD8+ TILs were not, likely due to a predominance of exhausted CD8+ T cells. In early-stage tumors, keratin-expressing cancer cells recruited Tregs via MHC class II, resulting in an inflammatory phenotype characterized by limited IFN{gamma} production and non-clonally expanded T cells. Additionally, IFI44L expression on macrophages caused immune exclusion by downregulating CD53 on T cells. Our findings reveal novel mechanisms of immune escape associated with localized disease and metastatic progression in HGSOC, highlighting potential targets to improve the efficacy of immunotherapy.