Unraveling tumor–immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy
- 1 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 52 (6), 582-593
- https://doi.org/10.1038/s41588-020-0630-5
Abstract
In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor–immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor–immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.Keywords
Funding Information
- Cancer Research UK (C14303/A17197, C14303/A17197, A22905, C14303/A17197, A19274, A15973, A19274, A19274)
- Target Ovarian Cancer (Cambridge-MM18)
- Brown Performance Innovation in Cancer Informatics Discovery Award
- Cancer Research UK Cambridge Institute and the Mexican National Council of Science and Technology (CONACyT).
- Breast Cancer Research Foundation
- Kaleidoscope of Hope GrantCycle for Survival Grant
- Kaleidoscope of Hope Grant
- The Mark Foundation
- Society of Memorial Sloan Kettering
- Marsha Rivkin OrganizationTranslational and Integrative Medicine Research Fund (MSKCC), Kaleidoscope of Hope
- Ovarian Cancer Research Alliance Liz Tilberis Award
- University of Cambridge Harding Distinguished Postgraduate Scholars Programme
- European Bioinformatics Institute
- EMBL-EBI & NIHR Cambridge Biomedical Research Centre Postdoctoral (EBPOD) program.
- Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation.
- Wellcome Trust
- Wellcome Trust grant through the Mathematical Genomics and Medicine programme.
- United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs
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