Abstract 2553: Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes
Authors: Vázquez-García Ignacio , Uhlitz Florian , Ceglia Nicholas , Lim Jamie L. , Wu Michelle , Mohibullah Neeman , Ruiz Arvin Eric B. , Boehm Kevin M. , Bojilova Viktoria , Fong Christopher J. , Funnell Tyler , Grewal Diljot , Havasov Eliyahu , Leung Samantha , Pasha Arfath , Patel Druv M. , Pourmaleki Maryam , Rusk Nicole , Shi Hongyu , Vanguri Rami , Williams Marc J. , Zhang Allen W. , Broach Vance , Chi Dennis S. , Paula Arnaud Da Cruz , Gardner Ginger J. , Kim Sarah H. , Lennon Matthew , Roche Kara Long , Sonoda Yukio , Zivanovic Oliver , Kundra Ritika , Viale Agnes , Bykov Yonina , Derakhshan Fatemeh N. , Geneslaw Luke , Maroldi Ana , Schietinger Andrea , Hollmann Travis J. , Bakhoum Samuel F. , Soslow Robert A. , Ellenson Lora H. , Abu-Rustum Nadeem , Aghajanian Carol , Friedman Claire F. , McPherson Andrew , Weigelt Britta ,   MSK SPECTRUM Consortium, Zamarin Dmitriy , Shah Sohrab P. 
Published: June 2022

Abstract
High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, a high degree of tumor heterogeneity and intraperitoneal spread. As immunotherapies have thus far proven ineffective in this disease, we sought to establish the determinants of immune recognition, avoidance and evasion in disease natural history to gain insight into the co-evolutionary processes underlying malignant progression and host immunity. Accordingly we linked mutational processes and anatomic sites of tumor foci as determinants of tumor microenvironment (TME) cellular phenotypes within and between patients using genome-based stratification of homologous recombination proficient (HRP) and deficient (HRD) disease subtypes, and profiling single cell phenotypes from ~1 million cells including cancer cells, T cells, myeloid cells and fibroblasts derived from single cell RNA sequencing, and in situ spatial profiling of histopathology, cancer cell, T cell and macrophage states of 160 tumor sites obtained from 42 treatment-naive patients. Mutational processes in HRD-Dup (BRCA1 mutant-like) tumors were associated with cancer cell-intrinsic JAK/STAT signaling and predominance of highly-differentiated dysfunctional CD8+ T cells in the TME; HRD-Del (BRCA2 mutant-like) tumors were associated with cancer cell-intrinsic NF-κB and TNFα signaling and expansion of M2-type macrophages; and foldback inversion (FBI, HRP) tumors were associated with cancer cell-intrinsic TGFβ signaling and overall immune exclusion, with a predominance of naive/central memory-like T cells. Increased neoantigen burden and HLA loss of heterozygosity (LOH) were defining genomic features of the HRD, but not FBI tumors. These mechanisms of escape from immune predation, with distinct signalling activity and losses of HLA allelic diversity in HRD tumors, connect evolutionary selection with immunological phenotypic states. Multi-region sampling revealed substantial spatial variation, highlighting site-specific properties of the ovary and fallopian tube as putative “immune-privileged” sites. These results establish that in patients with widespread intraperitoneal disease, the local properties of organ sites may determine malignant cell selection and immune pruning. Furthermore, we observed that spatial cellular topology is a major determinant of tumor-immune interactions by in situ protein measurements, revealing ubiquitous PD1-PDL1 interactions in HRD tumors. Together, our findings yield mechanistic insights for how distinct mutational processes in HGSOC lead to diverse patterns of within- and between- patient variation in immune resistance, which can be exploited to optimize future immuno-therapeutic treatment strategies.
Citation Format: Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L. Lim, Michelle Wu, Neeman Mohibullah, Arvin Eric B. Ruiz, Kevin M. Boehm, Viktoria Bojilova, Christopher J. Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M. Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J. Williams, Allen W. Zhang, Vance Broach, Dennis S. Chi, Arnaud Da Cruz Paula, Ginger J. Gardner, Sarah H. Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Yonina Bykov, Fatemeh N. Derakhshan, Luke Geneslaw, Ana Maroldi, Andrea Schietinger, Travis J. Hollmann, Samuel F. Bakhoum, Robert A. Soslow, Lora H. Ellenson, Nadeem Abu-Rustum, Carol Aghajanian, Claire F. Friedman, Andrew McPherson, Britta Weigelt, MSK SPECTRUM Consortium, Dmitriy Zamarin, Sohrab P. Shah. Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2553.