Estrogens determine the efficacy of cancer immunotherapy in obese males with melanoma
Although obesity is a major risk factor for cancer, it may also improve the response to cancer therapy. Here we investigated the impact of obesity on the efficacy of immune checkpoint inhibitors (ICI). In male mice, obesity promoted tumor growth but enhanced the response to ICI. This was associated with higher expression of immune-related genes within the tumor and enhanced infiltration of tumor-specific CD8+ T cells. Further, obesity in mice was associated with higher estrogen levels and enrichment of estrogen response genes in the tumor, and anti-programmed cell death 1 (anti-PD-1) efficacy was reduced upon administration of the aromatase inhibitor letrozole, which blocks the production of estrogens. Mechanistically, adipocyte-derived estrogens increased antigen presentation by dendritic cells and tumor-specific CD8+ T cell cytotoxicity. Last, overweight and obese men with melanoma responded better to ICI, with high estrogen levels being associated with improved response and survival. Our results suggest that estrogens may serve as a predictive factor of response to ICI in men with melanoma.
Authors
- Valérie Dutoit (ORCID: https://orcid.org/0000-0002-3469-4237)
- Montserrat Alvarez (ORCID: https://orcid.org/0000-0001-7206-073X)
- Eloïse Dupuychaffray (ORCID: https://orcid.org/0009-0004-0465-6856)
- Betül Taşkoparan (ORCID: https://orcid.org/0000-0003-1890-1547)
- Maxime Borgeaud (ORCID: https://orcid.org/0000-0003-1262-5641)
- Aurélien Pommier (ORCID: https://orcid.org/0009-0001-6540-1863)
- Carole Bourquin (ORCID: https://orcid.org/0000-0003-3862-4583)
- Eliana Marinari (ORCID: https://orcid.org/0000-0001-6526-5155)
- Olivier Preynat‐Seauve (ORCID: https://orcid.org/0000-0001-5364-967X)
- Aurélie Vuilleumier
- Clarissa D. Voegel (ORCID: https://orcid.org/0000-0002-5480-7956)
- Hélène Poinot (ORCID: https://orcid.org/0009-0006-8347-8430)
- Denis Migliorini (ORCID: https://orcid.org/0000-0003-0151-3222)
Institutions
- University of Geneva (CH)
- University of Bern (CH)
- HES-SO University of Applied Sciences and Arts Western Switzerland (CH)
- University Hospital of Bern (CH)
- University Hospital of Geneva (CH)
- Swiss Cancer Center Léman (CH)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-06-12
- DOI
- https://doi.org/10.1172/jci.insight.189758
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- National Science Foundation
- University of Bern
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Université de Genève
- Innosuisse - Schweizerische Agentur für Innovationsförderung
- Swiss Cancer Research Foundation
- Fondation ISREC
- Horizon 2020 Framework Programme
- Institute of Genetics and Genomics of Geneva