ABSTRACT High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, intratumoral heterogeneity and intraperitoneal spread. We investigated determinants of immune recognition and evasion in HGSOC to elucidate co- evolutionary processes underlying malignant progression and tumor immunity. Mutational processes and anatomic sites of tumor foci were key determinants of tumor microenvironment cellular phenotypes, inferred from whole genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive HGSOC patients. Homologous recombination-deficient (HRD)-Dup ( BRCA1 mutant-like) and HRD- Del ( BRCA2 mutant-like) tumors harbored increased neoantigen burden, inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly- differentiated dysfunctional CD8 + T cells. Foldback inversion (FBI, non-HRD) tumors exhibited elevated TGFβ signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies. HIGHLIGHTS Multi-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancer Anatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypes Tumor mutational processes impact mechanisms of immune control and immune evasion Spatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypes

Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes