Synapse - Ovarian cancer mutational processes drive site-specific immune evasion

Ovarian cancer mutational processes drive site-specific immune evasion Journal Article

Authors:	Vázquez-García, I.; Uhlitz, F.; Ceglia, N.; Lim, J. L. P.; Wu, M.; Mohibullah, N.; Niyazov, J.; Ruiz, A. E. B.; Boehm, K. M.; Bojilova, V.; Fong, C. J.; Funnell, T.; Grewal, D.; Havasov, E.; Leung, S.; Pasha, A.; Patel, D. M.; Pourmaleki, M.; Rusk, N.; Shi, H.; Vanguri, R.; Williams, M. J.; Zhang, A. W.; Broach, V.; Chi, D. S.; Da Cruz Paula, A.; Gardner, G. J.; Kim, S. H.; Lennon, M.; Long Roche, K.; Sonoda, Y.; Zivanovic, O.; Kundra, R.; Viale, A.; Derakhshan, F. N.; Geneslaw, L.; Issa Bhaloo, S.; Maroldi, A.; Nunez, R.; Pareja, F.; Stylianou, A.; Vahdatinia, M.; Bykov, Y.; Grisham, R. N.; Liu, Y. L.; Lakhman, Y.; Nikolovski, I.; Kelly, D.; Gao, J.; Schietinger, A.; Hollmann, T. J.; Bakhoum, S. F.; Soslow, R. A.; Ellenson, L. H.; Abu-Rustum, N. R.; Aghajanian, C.; Friedman, C. F.; McPherson, A.; Weigelt, B.; Zamarin, D.; Shah, S. P.
Article Title:	Ovarian cancer mutational processes drive site-specific immune evasion
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. © 2022, The Author(s).
Keywords:	clinical article; human tissue; gene mutation; human cell; genetics; mutation; histopathology; cd8+ t lymphocyte; cd8-positive t-lymphocytes; ovarian neoplasms; phenotype; homologous recombination; tumor localization; cancer immunotherapy; ovary cancer; transforming growth factor beta; inflammation; cohort analysis; immunofluorescence; pathology; tumor suppressor gene; ovary tumor; tumor immunity; cystadenocarcinoma, serous; memory; hla antigen; cystadenocarcinoma; personalized medicine; memory t lymphocyte; tumor microenvironment; immune evasion; tumor escape; cancer; humans; human; female; article; whole genome sequencing; early cancer diagnosis; high grade serous ovarian cancer; tgf beta signaling; single cell rna seq; multiomics
Journal Title:	Nature
Volume:	612
Issue:	7941
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2022-12-22
Start Page:	778
End Page:	786
Language:	English
DOI:	10.1038/s41586-022-05496-1
PUBMED:	36517593
PROVIDER:	scopus
PMCID:	PMC9771812
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85143886749&doi=10.1038%2fs41586-022-05496-1&partnerID=40&md5=df987ebf65c71c43f98df81f1bc69cc4
Notes:	Article -- Export Date: 3 January 2023 -- Source: Scopus