期刊
NATURE GENETICS
卷 52, 期 6, 页码 582-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0630-5
关键词
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资金
- Marsha Rivkin Organization, Memorial Sloan Kettering Cancer Center, Translational and Integrative Medicine Research Fund (MSKCC)
- Kaleidoscope of Hope
- Kaleidoscope of Hope grant
- MSK Cancer Center Support Grant of the National Cancer Institute at the National Institutes of Health [P30 CA008748]
- Ovarian Cancer Research Alliance Liz Tilberis Award
- Wellcome Trust
- Cancer Research UK [C14303/A17197, A22905, A19274, A15973]
- Brown Performance Innovation in Cancer Informatics Discovery Award [BD523775]
- Target Ovarian Cancer Translational Project Grant (Cambridge) [MM18]
- Mark Foundation for Cancer Research
- Cancer Research UK Cambridge Centre [C9685/A25177]
- Cancer Research UK Cambridge Institute
- Mexican National Council of Science and Technology (CONACyT)
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- Breast Cancer Research Foundation
- Department of Defense Congressionally Directed Medical Research Programs [W81XWH-15-1-0547, GC229671]
- EMBL-EBI
- NIHR Cambridge Biomedical Research Centre (EBPOD)
- University of Cambridge Harding Distinguished Postgraduate Scholars Programme
- University of Cambridge
- Hutchison Whampoa Limited
- Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation
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. Immunogenomic analyses of advanced high-grade serous ovarian cancer samples before and after neoadjuvant chemotherapy show that the tumor-immune microenvironment is intrinsically heterogeneous and that chemotherapy induces local immune activation.
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