RT Journal Article
SR Electronic
T1 Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.24.454519
DO 10.1101/2021.08.24.454519
A1 Ignacio Vázquez-García
A1 Florian Uhlitz
A1 Nicholas Ceglia
A1 Jamie L.P. Lim
A1 Michelle Wu
A1 Neeman Mohibullah
A1 Arvin Eric B. Ruiz
A1 Kevin M. Boehm
A1 Viktoria Bojilova
A1 Christopher J. Fong
A1 Tyler Funnell
A1 Diljot Grewal
A1 Eliyahu Havasov
A1 Samantha Leung
A1 Arfath Pasha
A1 Druv M. Patel
A1 Maryam Pourmaleki
A1 Nicole Rusk
A1 Hongyu Shi
A1 Rami Vanguri
A1 Marc J. Williams
A1 Allen W. Zhang
A1 Vance Broach
A1 Dennis Chi
A1 Arnaud Da Cruz Paula
A1 Ginger J. Gardner
A1 Sarah H. Kim
A1 Matthew Lennon
A1 Kara Long Roche
A1 Yukio Sonoda
A1 Oliver Zivanovic
A1 Ritika Kundra
A1 Agnes Viale
A1 Fatemeh N. Derakhshan
A1 Luke Geneslaw
A1 Ana Maroldi
A1 Rahelly Nunez
A1 Fresia Pareja
A1 Anthe Stylianou
A1 Mahsa Vahdatinia
A1 Yonina Bykov
A1 Rachel N. Grisham
A1 Ying L. Liu
A1 Yulia Lakhman
A1 Ines Nikolovski
A1 Daniel Kelly
A1 Jianjiong Gao
A1 Andrea Schietinger
A1 Travis J. Hollmann
A1 Samuel F. Bakhoum
A1 Robert A. Soslow
A1 Lora H. Ellenson
A1 Nadeem R. Abu-Rustum
A1 Carol Aghajanian
A1 Claire F. Friedman
A1 Andrew McPherson
A1 Britta Weigelt
A1 Dmitriy Zamarin
A1 Sohrab P. Shah
YR 2021
UL http://biorxiv.org/content/early/2021/08/25/2021.08.24.454519.abstract
AB 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.HIGHLIGHTSMulti-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancerAnatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypesTumor mutational processes impact mechanisms of immune control and immune evasionSpatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypesCompeting Interest StatementSPS 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.