Ovarian cancer mutational processes drive site-specific immune evasion

Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L. P. Lim, Michelle Wu, Neeman Mohibullah, Juliana Niyazov, 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, Fatemeh N. Derakhshan, Luke Geneslaw, Shirin Issa Bhaloo, Ana Maroldi, Rahelly Nunez, Fresia Pareja, Anthe Stylianou, Mahsa Vahdatinia, Yonina Bykov, Rachel N. Grisham, Ying L. Liu, Yulia Lakhman, Ines Nikolovski, Daniel Kelly, Jianjiong Gao, Andrea Schietinger, Travis J. Hollmann, Samuel F. Bakhoum, Robert A. Soslow, Lora H. Ellenson, Nadeem R. Abu-Rustum, Carol Aghajanian, Claire F. Friedman, Andrew McPherson, Britta Weigelt, Dmitriy Zamarin () and Sohrab P. Shah ()
Additional contact information
Ignacio Vázquez-García: Memorial Sloan Kettering Cancer Center
Florian Uhlitz: Memorial Sloan Kettering Cancer Center
Nicholas Ceglia: Memorial Sloan Kettering Cancer Center
Jamie L. P. Lim: Memorial Sloan Kettering Cancer Center
Michelle Wu: Memorial Sloan Kettering Cancer Center
Neeman Mohibullah: Memorial Sloan Kettering Cancer Center
Juliana Niyazov: Memorial Sloan Kettering Cancer Center
Arvin Eric B. Ruiz: Memorial Sloan Kettering Cancer Center
Kevin M. Boehm: Memorial Sloan Kettering Cancer Center
Viktoria Bojilova: Memorial Sloan Kettering Cancer Center
Christopher J. Fong: Memorial Sloan Kettering Cancer Center
Tyler Funnell: Memorial Sloan Kettering Cancer Center
Diljot Grewal: Memorial Sloan Kettering Cancer Center
Eliyahu Havasov: Memorial Sloan Kettering Cancer Center
Samantha Leung: Memorial Sloan Kettering Cancer Center
Arfath Pasha: Memorial Sloan Kettering Cancer Center
Druv M. Patel: Memorial Sloan Kettering Cancer Center
Maryam Pourmaleki: Memorial Sloan Kettering Cancer Center
Nicole Rusk: Memorial Sloan Kettering Cancer Center
Hongyu Shi: Memorial Sloan Kettering Cancer Center
Rami Vanguri: Memorial Sloan Kettering Cancer Center
Marc J. Williams: Memorial Sloan Kettering Cancer Center
Allen W. Zhang: Memorial Sloan Kettering Cancer Center
Vance Broach: Memorial Sloan Kettering Cancer Center
Dennis S. Chi: Memorial Sloan Kettering Cancer Center
Arnaud Da Cruz Paula: Memorial Sloan Kettering Cancer Center
Ginger J. Gardner: Memorial Sloan Kettering Cancer Center
Sarah H. Kim: Memorial Sloan Kettering Cancer Center
Matthew Lennon: Memorial Sloan Kettering Cancer Center
Kara Long Roche: Memorial Sloan Kettering Cancer Center
Yukio Sonoda: Memorial Sloan Kettering Cancer Center
Oliver Zivanovic: Memorial Sloan Kettering Cancer Center
Ritika Kundra: Memorial Sloan Kettering Cancer Center
Agnes Viale: Memorial Sloan Kettering Cancer Center
Fatemeh N. Derakhshan: Memorial Sloan Kettering Cancer Center
Luke Geneslaw: Memorial Sloan Kettering Cancer Center
Shirin Issa Bhaloo: Memorial Sloan Kettering Cancer Center
Ana Maroldi: Memorial Sloan Kettering Cancer Center
Rahelly Nunez: Memorial Sloan Kettering Cancer Center
Fresia Pareja: Memorial Sloan Kettering Cancer Center
Anthe Stylianou: Memorial Sloan Kettering Cancer Center
Mahsa Vahdatinia: Memorial Sloan Kettering Cancer Center
Yonina Bykov: Memorial Sloan Kettering Cancer Center
Rachel N. Grisham: Memorial Sloan Kettering Cancer Center
Ying L. Liu: Memorial Sloan Kettering Cancer Center
Yulia Lakhman: Memorial Sloan Kettering Cancer Center
Ines Nikolovski: Memorial Sloan Kettering Cancer Center
Daniel Kelly: Memorial Sloan Kettering Cancer Center
Jianjiong Gao: Memorial Sloan Kettering Cancer Center
Andrea Schietinger: Weill Cornell Medical Center
Travis J. Hollmann: Memorial Sloan Kettering Cancer Center
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Robert A. Soslow: Memorial Sloan Kettering Cancer Center
Lora H. Ellenson: Memorial Sloan Kettering Cancer Center
Nadeem R. Abu-Rustum: Memorial Sloan Kettering Cancer Center
Carol Aghajanian: Memorial Sloan Kettering Cancer Center
Claire F. Friedman: Memorial Sloan Kettering Cancer Center
Andrew McPherson: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Dmitriy Zamarin: Memorial Sloan Kettering Cancer Center
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 612, issue 7941, 778-786

Abstract: Abstract High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1–4 patterned by distinct mutational processes5,6, tumour heterogeneity7–9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11–13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling 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 tumours 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.

Date: 2022
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DOI: 10.1038/s41586-022-05496-1

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