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Ovarian cancer mutational processes drive site-specific immune evasion.

ABSTRACT: High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability^1-4 patterned by distinct mutational processes^5,6, tumour heterogeneity^7-9 and intraperitoneal spread^7,8,10. Immunotherapies have had limited efficacy in HGSOC^11-13, 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.

SUBMITTER: Vazquez-Garcia I

PROVIDER: S-EPMC9771812 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Ovarian cancer mutational processes drive site-specific immune evasion.

Vázquez-García Ignacio I Uhlitz Florian F Ceglia Nicholas N Lim Jamie L P JLP Wu Michelle M Mohibullah Neeman N Niyazov Juliana J Ruiz Arvin Eric B AEB Boehm Kevin M KM Bojilova Viktoria V Fong Christopher J CJ Funnell Tyler T Grewal Diljot D Havasov Eliyahu E Leung Samantha S Pasha Arfath A Patel Druv M DM Pourmaleki Maryam M Rusk Nicole N Shi Hongyu H Vanguri Rami R Williams Marc J MJ Zhang Allen W AW Broach Vance V Chi Dennis S DS Da Cruz Paula Arnaud A Gardner Ginger J GJ Kim Sarah H SH Lennon Matthew M Long Roche Kara K Sonoda Yukio Y Zivanovic Oliver O Kundra Ritika R Viale Agnes A Derakhshan Fatemeh N FN Geneslaw Luke L Issa Bhaloo Shirin S Maroldi Ana A Nunez Rahelly R Pareja Fresia F Stylianou Anthe A Vahdatinia Mahsa M Bykov Yonina Y Grisham Rachel N RN Liu Ying L YL Lakhman Yulia Y Nikolovski Ines I Kelly Daniel D Gao Jianjiong J Schietinger Andrea A Hollmann Travis J TJ Bakhoum Samuel F SF Soslow Robert A RA Ellenson Lora H LH Abu-Rustum Nadeem R NR Aghajanian Carol C Friedman Claire F CF McPherson Andrew A Weigelt Britta B Zamarin Dmitriy D Shah Sohrab P SP

Nature 20221214 7941

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 ...[more]

PMID: 36517593

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Project description:BackgroundDespite breakthroughs in treatment, ovarian cancer (OC) remains one of the most lethal gynecological malignancies, with an increasing age-standardized mortality rate. This underscores an urgent need for novel biomarkers and therapeutic targets. Although growth factor receptor-bound protein 7 (GRB7) is implicated in cell signaling and tumorigenesis, its expression pattern and clinical implications in OC remain poorly characterized.MethodsTo systematically investigate GRB7's expression in OC, our study utilized extensive datasets from TCGA, GTEx, CCLE, and GEO. The prognostic significance of GRB7 was evaluated by means of Kaplan-Meier and Cox regression analyses. Using a correlation analysis and gene set enrichment analysis, relationships between GRB7's expression and gene networks, immune cell infiltration and immunotherapy response were investigated. In vitro experiments were conducted to confirm GRB7's function in the biology of OC.ResultsCompared to normal tissues, OC tissues exhibited a substantial upregulation of GRB7. Reduced overall survival, disease-specific survival, and disease-free interval were all connected with high GRB7 mRNA levels. The network study demonstrated that GRB7 is involved in pathways relevant to the course of OC and has a positive connection with several key driver genes. Notably, GRB7's expression was linked to the infiltration of M2 macrophage and altered response to immunotherapy. Data from single-cell RNA sequencing data across multiple cancer types indicated GRB7's predominant expression in malignant cells. Moreover, OC cells with GRB7 deletion showed decreased proliferation and migration, as well as increased susceptibility to T cell-mediated cytotoxicity.ConclusionWith respect to OC, our results validated GRB7 as a viable prognostic biomarker and a promising therapeutic target, providing information about its function in tumorigenesis and immune modulation. GRB7's preferential expression in malignant cells highlights its significance in the biology of cancer and bolsters the possibility that it could be useful in enhancing the effectiveness of immunotherapy.

Dataset Information

Ovarian cancer mutational processes drive site-specific immune evasion.

Publications

Ovarian cancer mutational processes drive site-specific immune evasion.

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