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Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation

Abstract

Treatment of high-grade serous ovarian cancer (HGSOC) remains challenging. Although HGSOC can potentially be responsive to immunotherapy owing to endogenous immunity at the molecular or T cell level, immunotherapy for this disease has fallen short of expectations to date. This Review proposes a working classification for HGSOC based on the presence or absence of intraepithelial T cells, and elaborates the putative mechanisms that give rise to such immunophenotypes. These differences might explain the failures of existing immunotherapies, and suggest that rational therapeutic approaches tailored to each immunophenotype might meet with improved success. In T cell-inflamed tumours, treatment could focus on mobilizing pre-existing immunity and strengthening the activation of T cells embedded in intraepithelial tumour myeloid niches. Conversely, in immune-excluded and immune-desert tumours, treatment could focus on restoring inflammation by reprogramming myeloid cells, stromal cells and vascular epithelial cells. Poly(ADP-ribose) polymerase (PARP) inhibitors, low-dose radiotherapy, epigenetic drugs and anti-angiogenesis therapy are among the tools available to restore T cell infiltration in HGSOC tumours and could be implemented in combination with vaccines and redirected T cells.

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Fig. 1: Immunophenotypic classification of high-grade serous ovarian cancer.
Fig. 2: Cellular crosstalk in the tumour microenvironment orchestrates the T cell-inflamed immunophenotype of high-grade serous ovarian cancer.
Fig. 3: Inducing anticancer immune responses in high-grade serous ovarian cancer tumours with an immune-excluded or cold immunophenotype.

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Acknowledgements

The authors’ research work is supported by the Ludwig Institute for Cancer Research and NIH grants P50 CA083638 National Cancer Institute Specialized Program of Research Excellence (SPORE) in Ovarian Cancer, R01-CA116779 and R01-CA098951; grants from the Pennsylvania Department of Health (the department specifically disclaims responsibility for any analyses, interpretations or conclusions); and grants from the Ovarian Cancer Immunotherapy Initiative, Ovarian Cancer Research Fund, Sidney Kimmel Foundation, Gynecologic Cancer Foundation, Mary Kay Ash Foundation, Sandy Rollman Ovarian Cancer Foundation, American Cancer Society, Cancer Foundation, Biltema Foundation and Paul Matson Foundation (all to G.C.); partly supported by the Department of Defense (DOD) Early Career Investigator (ECI) W81XWH2210703 Award OC210038 (to D.D.L.) (Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense); and supported by OvaCure and the Rivkin Center for Ovarian Cancer (to L.E.K.).

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L.E.K. and D.D.L. contributed to researching data for the article and writing the initial draft. All authors contributed to reviewing and/or editing of the manuscript before submission. In addition, G.C. and D.D.L. contributed to discussions of the article content.

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Correspondence to George Coukos.

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G.C. declares that he has received grants or research support from or is a co-investigator in clinical trials conducted by Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Iovance, Kite, Roche and Tigen. Lausanne University Hospital has received honoraria for advisory services provided by G.C. to AstraZeneca, Bristol-Myers Squibb, Hoffmann-La Roche, MSD and Geneos Therapeutics. G.C. holds patents related to antibodies and vaccines targeting the tumour vasculature as well as technologies related to T cell expansion and engineering of T cell therapy, for which G.C. receives royalties from the University of Pennsylvania. L.E.K. declares that she has received honoraria for advisory services provided to Geneos Therapeutics and AstraZeneca. D.D.L. declares no competing interests.

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Kandalaft, L.E., Dangaj Laniti, D. & Coukos, G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat Rev Cancer (2022). https://doi.org/10.1038/s41568-022-00503-z

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