Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer
Authors: Brad H. Nelson, Phineas T. Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald L.I. Stevens, Shreena Kalaria, Karanvir Singh, Céline M. Laumont, Elena Moss, Aliya Alimujiang, Nicola S. Meagher, Adelyn Bolithon, Sian Fereday, Catherine J. Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L. Goode, Anthony N. Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A. Doherty, Holly R. Harris, Kara L. Cushing-Haugen, Michael S. Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E. Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul D.P. Pharoah, Jessica Boros, Alison H. Brand, Paul R. Harnett, Raghwa Sharma, Jonathan L. Hecht, Naoko Sasamoto, Kathryn L. Terry, Beth Y. Karlan, Jenny Lester, Michael E. Carney, Marc T. Goodman, Brenda Y. Hernandez, Lynne R. Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A. Fasching, Christiani Bisinotto, Francisco José Candido dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S. Cook, Nhu D. Le, Aleksandra Gentry-Maharaj, Usha Menon, María J. García, Cristina Rodriguez-Antona, Kyo M. Farrington, Linda E. Kelemen, Stefan Kommoss, Annette Staebler, Dale W. Garsed, James D. Brenton, Anna M. Piskorz, David D.L. Bowtell, Anna DeFazio, Susan J. Ramus, Malcolm C. Pike, Celeste Leigh Pearce
Journal: Journal of Clinical Investigation (2024)

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.