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

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 ### Competing Interest Statement SPS is a consultant and shareholder of Canexia Health Inc. DZ reports research funding to MSK from AstraZeneca, Genentech, and Plexxikon; personal fees from Synlogic Therapeutics, Hookipa Biotech, Agenus, Synthekine, Memgen, Mana Therapeutics, Tessa Therapeutics, and Xencor; stock options from Accurius, Calidi Biotherapeutics, and Immunos. DZ is an inventor on a patent concerning the use of Newcastle Disease Virus as a cancer therapeutic, licensed to Merck. CFF reports research funding to the institution from Merck, AstraZeneca, Genentech, Bristol Myer Squibb, Taiho and Seattle Genetics; uncompensated membership of a scientific advisory board for Merck and Genentech; and is a consultant for OncLive, Aptitude Health, and Seattle Genetics, all outside the scope of this manuscript. CA reports grants from Clovis, Genentech, AbbVie and AstraZeneca, personal fees from Tesaro, Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca/Merck and Repare Therapeutics, outside the submitted work. NRAR reports grants to MSK from Stryker/Novadaq and GRAIL, outside the submitted work. DSC is on the medical advisory board of Apyx Medical Co, Verthermia Acquio Inc and Biom'up, and is a stockholder of Intuitive Surgical Inc and TransEnterix Inc. RNG reports funding from GSK, Mateon Therapeutics, Regeneron, Clovis, Context Therapeutics, EMD Serono, MCM Education, OncLive, Aptitude Health and Prime Oncology, outside this work. YLL reports research funding from AstraZeneca and GSK/Tesaro outside this work. YL is a shareholder of Y-mAbs Therapeutics Inc. TJH receives research funding from Bristol Myers Squibb, Calico Labs and the Parker Institute for Cancer Immunotherapy. SFB owns equity in, receives compensation from, and serves as a consultant and the Scientific Advisory Board and Board of Directors of Volastra Therapeutics Inc. SFB has also consulted for Sanofi, received sponsored travel from the Prostate Cancer Foundation, and both travel and compensation from Cancer Research UK. BW reports ad hoc membership of the scientific advisory board of Repare Therapeutics, outside the submitted work.