Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer.
- 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.
- Authors:
- BH Nelson, PT Hamilton, MT Phung, K Milne, B Harris, S Thornton, DL Stevens, S Kalaria, K Singh, CM Laumont, E Moss, A Alimujiang, NS Meagher, A Bolithon, S Fereday, CJ Kennedy, J Hendley, D Ariyaratne, K Alsop, N Traficante, EL Goode, AN Karnezis, H Shen, J Richardson, C McKinnon Deurloo, A Chase, B Grout, JA Doherty, HR Harris, KL Cushing-Haugen, MS Anglesio, K Heinze, D Huntsman, A Talhouk, GE Hanley, J Alsop, M Jimenez-Linan, PD Pharoah, J Boros, AH Brand, PR Harnett, R Sharma, JL Hecht, N Sasamoto, KL Terry, BY Karlan, J Lester, ME Carney, MT Goodman, BY Hernandez, LR Wilkens, S Behrens, R Turzanski Fortner, PA Fasching, C Bisinotto, FJ Candido Dos Reis, P Ghatage, M Köbel, E Elishaev, F Modugno, LS Cook, ND Le, A Gentry-Maharaj, U Menon, MJ García, C Rodriguez-Antona, KM Farrington, LE Kelemen, S Kommoss, A Staebler, DW Garsed, JD Brenton, AM Piskorz, DD Bowtell, A DeFazio, SJ Ramus, MC Pike, CL Pearce
- Journal:
- J Clin Invest
- Publication date:
- 29th Oct 2024
- Full text
- DOI