Abstract IA021: Mutational processes as determinants of immune evasion in ovarian cancer

Abstract High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, tumor heterogeneity and intraperitoneal spread. Immunotherapies have had limited efficacy in HGSOC, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumor foci determine the immunological states of the tumor microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumors harbored inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumors exhibited elevated immunosuppressive TGFβ signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumors and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research. Citation Format: Sohrab P. Shah. Mutational processes as determinants of immune evasion in ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr IA021.