Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer
- Author(s)
- Nelson, BH; Hamilton, PT; Phung, MT; Milne, K; Harris, B; Thornton, S; Stevens, DL; Kalaria, S; Singh, K; Laumont, CM; Moss, E; Alimujiang, A; Meagher, NS; Bolithon, A; Fereday, S; Kennedy, CJ; Hendley, J; Ariyaratne, D; Alsop, K; Traficante, N; Goode, EL; Karnezis, AN; Shen, H; Richardson, J; McKinnon Deurloo, C; Chase, A; Grout, B; Doherty, JA; Harris, HR; Cushing-Haugen, KL; Anglesio, MS; Heinze, K; Huntsman, D; Talhouk, A; Hanley, GE; Alsop, J; Jimenez-Linan, M; Pharoah, PD; Boros, J; Brand, AH; Harnett, PR; Sharma, R; Hecht, JL; Sasamoto, N; Terry, KL; Karlan, BY; Lester, J; Carney, ME; Goodman, MT; Hernandez, BY; Wilkens, LR; Behrens, S; Turzanski Fortner, R; Fasching, PA; Bisinotto, C; Candido Dos Reis, FJ; Ghatage, P; Köbel, M; Elishaev, E; Modugno, F; Cook, LS; Le, ND; Gentry-Maharaj, A; Menon, U; García, MJ; Rodriguez-Antona, C; Farrington, KM; Kelemen, LE; Kommoss, S; Staebler, A; Garsed, DW; Brenton, JD; Piskorz, AM; Bowtell, DD; DeFazio, A; Ramus, SJ; Pike, MC; Pearce, CL;
- Journal Title
- Journal of Clinical Investigation
- Publication Type
- Online publication before print
- Abstract
- BACKGROUND: Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS: We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS: Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS: The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING: Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.
- Keywords
- Cancer; Cellular immune response; Epidemiology; Immunology; Oncology
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1172/jci179501
- Open Access at Publisher's Site
https://doi.org/10.1172/jci179501- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-12-03 12:10:37
Last Modified: 2024-12-03 12:11:43