Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

Eleonora Ghisoni¹, Fabrizio Benedetti², Aspram Minasyan², Mathieu Desbuisson², Paula Cunnea³, Alizée J Grimm², Noémie Fahr², Charlotte Capt², Nicolas Rayroux², Flavia De Carlo², Doga C Gulhan⁴, Julien Dagher⁵, David Barras², Matteo Morotti², Juan A Marín-Jiménez⁶, Bovannak Stewen Chap², Tania Santoro², Giulia Spagnol⁷, Mapi Fleury⁸, Katerina Fortis⁹, Julien Dorier¹⁰, Mary K Townsend¹¹, Stephanie Tissot⁹, Sylvie Rusakiewicz⁹, Humberto J Ferreira², Anne I Kraemer², Michal Bassani-Stenberg², Elizabeth M Swisher¹², Lana A Kandalaft¹³, Spyridon A Mastroyannis¹⁴, Kathleen T Montone¹⁵, Daniel J Powell Jr¹⁵, Susana Banerjee¹⁶, Kathryn L Terry¹⁷, Shelley S Tworoger¹¹, Mikaël J Pittet¹⁸, Janos L Tanyi¹⁴, George Coukos¹, Melissa A Merritt¹⁹, Christina Fotopoulou³, Jose R Conejo-Garcia²⁰, Denarda Dangaj Laniti²¹

Affiliations

¹ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
² Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland.
³ Division of Cancer, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
⁴ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Massachusetts General Hospital Cancer Center and Harvard Medical School Department of Medicine, Boston, MA, USA.
⁵ Unit of Translational Oncopathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.
⁶ Cancer Immunotherapy Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Department of Women and Children's Health, Unit of Gynecology and Obstetrics, University of Padua, Padua, Italy.
⁸ Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
⁹ Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
¹⁰ Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
¹¹ Division of Oncological Sciences, OHSU Knight Cancer Institute, Portland, OR, USA.
¹² Department of Obstetrics/Gynecology, University of Washington, Seattle, WA, USA.
¹³ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
¹⁴ Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
¹⁷ Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁸ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
¹⁹ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
²⁰ Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC 27707, USA.
²¹ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland. Electronic address: denarda.dangaj@chuv.ch.

PMID: 40749672
DOI: 10.1016/j.ccell.2025.07.005

Free article

Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

Eleonora Ghisoni et al. Cancer Cell. 2025.

Free article

. 2025 Aug 11;43(8):1568-1586.e10.

doi: 10.1016/j.ccell.2025.07.005. Epub 2025 Jul 31.

Authors

Affiliations

¹ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
² Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland.
³ Division of Cancer, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
⁴ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Massachusetts General Hospital Cancer Center and Harvard Medical School Department of Medicine, Boston, MA, USA.
⁵ Unit of Translational Oncopathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.
⁶ Cancer Immunotherapy Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Department of Women and Children's Health, Unit of Gynecology and Obstetrics, University of Padua, Padua, Italy.
⁸ Immuno-oncology Service, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
⁹ Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
¹⁰ Bioinformatics Competence Center, University of Lausanne, Lausanne, Switzerland.
¹¹ Division of Oncological Sciences, OHSU Knight Cancer Institute, Portland, OR, USA.
¹² Department of Obstetrics/Gynecology, University of Washington, Seattle, WA, USA.
¹³ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.
¹⁴ Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁶ The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
¹⁷ Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁸ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland; Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
¹⁹ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
²⁰ Department of Integrative Immunobiology, Duke School of Medicine, Durham, NC 27707, USA.
²¹ Department of Oncology, Lausanne University Hospital; Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne (UNIL); Agora Cancer Research Center, Lausanne, Switzerland. Electronic address: denarda.dangaj@chuv.ch.

PMID: 40749672
DOI: 10.1016/j.ccell.2025.07.005

Abstract

Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1^mut tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE₂ signaling. Conversely, recurrent Brca1^wt tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoE^high tumor associated macrophages (TAMs) and Nduf4l2^high/Galectin3^high malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.

Keywords: PGE(2) signaling; TREM2; immune phenotype; myeloid-T cell networks; ovarian cancer; recurrence; tumor microenvironment.

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Conflict of interest statement

Declaration of interests E.G. received honoraria from AbbVie and Astrazeneca. C.F. received honoraria from Ethicon, GSK, Astra Zeneca/MSD, Tesaro, Clovis, Sequana and Roche, outside of the submitted work. M.M. is a current employee of the CDR-Life company. SB received research funding to the institution from Astrazeneca and GlaxoSmithKline; personal honoraria fees for advisory boards and/or educational activities from Abbvie, Astrazeneca, Biontech, Eisai, Gilead, GlaxoSmithKline, Gray Wolf Therapeutics, Immunogen, Incyte, ITM Oncologics, Merck Sharpe Dohme, Myriad, Pharmaand, Takeda, TORL BioTherapeutics, Verastem and Zymeworks; Travel expenses from Astrazeneca, GlaxoSmithKline and Verastem. In the last three years G.C. has received grants, research support or has been coinvestigator in clinical trials by Bristol-Myers Squibb, Tigen Pharma, Iovance, F. Hoffmann-La Roche AG, Boehringer Ingelheim. The Lausanne University Hospital (CHUV) has received honoraria for advisory services G.C. has provided to Genentech, AstraZeneca AG, EVIR. Patents related to the NeoTIL technology from the Coukos laboratory have been licensed by the Ludwig Institute, on behalf also of the University of Lausanne and the CHUV, to Tigen Pharma. G.C. has previously received royalties from the University of Pennsylvania for CAR-T cell therapy licensed to Novartis and Immunity Therapeutics. J.R.C.-G. has stock options with Anixa Biosciences and Alloy Therapeutics; receives licensing fees from Anixa Biosciences and consulting fees from Alloy Therapeutics; and is co-founder of Cellepus Therapeutics. D.D.L has received research grant from Hoffmann-La Roche AG and 10xGenomics. All other authors declared no competing interests.

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Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

Affiliations

Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical

Miscellaneous