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, Sohrab P. Shah

Abstract

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1,2,3,4 patterned by distinct mutational processes5,6, tumour heterogeneity7,8,9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11,12,13, 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.

Datasets

1. MSK SPECTRUM - CD4+ T cells, CD8+ T cells, ILCs and NK cells
Metadata
doublet
batch
patient_id
Phase
RNA_snn_res.0.3
seurat_clusters
cell_type_super
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cluster_extended
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tissue_type
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disease
organism
sex
tissue
self_reported_ethnicity
development_stage
False221310 cells
True5 cells
Preview
Ovarian cancer mutational processes drive site-specific immune evasion
2. MSK SPECTRUM - Malignant and non-malignant epithelial cells
Metadata
doublet
batch
patient_id
Phase
RNA_snn_res.0.3
seurat_clusters
cell_type_super
RNA_snn_res.0.1
RNA_snn_res.0.2
cluster_label
author_cell_type
organism_ontology_term_id
cell_type_ontology_term_id
tissue_ontology_term_id
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author_tumor_supersite
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author_procedure_type
tissue_type
cell_type
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disease
organism
sex
tissue
self_reported_ethnicity
development_stage
False211619 cells
True5 cells
Preview
Ovarian cancer mutational processes drive site-specific immune evasion
3. MSK SPECTRUM - Macrophages
Metadata
doublet
batch
patient_id
Phase
RNA_snn_res.0.3
seurat_clusters
cell_type_super
cluster_label
author_cell_type
organism_ontology_term_id
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author_procedure_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
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development_stage
False166691 cells
True204 cells
Preview
Ovarian cancer mutational processes drive site-specific immune evasion
4. MSK SPECTRUM - Dendritic cells
Metadata
doublet
batch
patient_id
Phase
RNA_snn_res.0.3
seurat_clusters
cell_type_super
cluster_label
author_cell_type
organism_ontology_term_id
cell_type_ontology_term_id
tissue_ontology_term_id
assay_ontology_term_id
suspension_type
disease_ontology_term_id
self_reported_ethnicity_ontology_term_id
development_stage_ontology_term_id
sex_ontology_term_id
donor_id
author_tumor_supersite
author_tumor_site
author_tumor_subsite
author_sort_parameters
author_therapy
author_procedure
author_procedure_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
False24002 cells
True23 cells
Preview
Ovarian cancer mutational processes drive site-specific immune evasion

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Source data

https://cellxgene.cziscience.com/collections/4796c91c-9d8f-4692-be43-347b1727f9d8

Alias names

phs002857, GSE180661, MSK SPECTRUM, PMID36517593, PMC9771812

Cite this study

Vázquez-García, I., Uhlitz, F., Ceglia, N., Lim, J.L., Wu, M., Mohibullah, N., Niyazov, J., Ruiz, A.E.B., Boehm, K.M., Bojilova, V. and Fong, C.J., 2022. Ovarian cancer mutational processes drive site-specific immune evasion. Nature, 612(7941), pp.778-786. https://doi.org/10.1038/s41586-022-05496-1