Estrogens determine the efficacy of cancer immunotherapy in obese males with melanoma
Eloïse Dupuychaffray, … , Carole Bourquin, Aurélien Pommier
Eloïse Dupuychaffray, … , Carole Bourquin, Aurélien Pommier
Published June 16, 2025
Citation Information: JCI Insight. 2025;10(14):e189758. https://doi.org/10.1172/jci.insight.189758.
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Research Article Immunology Oncology

Estrogens determine the efficacy of cancer immunotherapy in obese males with melanoma

Abstract

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

Eloïse Dupuychaffray, Hélène Poinot, Aurélie Vuilleumier, Maxime Borgeaud, Montserrat Alvarez, Betül Taskoparan, Olivier Preynat-Seauve, Clarissa D. Voegel, Eliana Marinari, Denis Migliorini, Valérie Dutoit, Carole Bourquin, Aurélien Pommier

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Figure 1

Obesity confers sensitivity to anti–PD-1 treatment in mice bearing B16-F10 tumors.

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Obesity confers sensitivity to anti–PD-1 treatment in mice bearing B16-F...
Male C57BL/6 mice fed with a Western diet to induce obesity or with a control diet were subcutaneously injected with B16-F10 tumor cells. After the development of palpable tumors, mice received either anti–PD-1 or isotype control. (A) Tumor growth in nonobese (dotted line) or obese mice (solid line), receiving anti–PD-1 (red) or isotype control (blue). Black arrows indicate anti–PD-1 or isotype treatment (n = 6–10/group). Two-way ANOVA with Tukey’s post hoc test was used to assess statistical significance. *P < 0.05, **P < 0.01. (B) Volcano plots of RNA-sequencing data from B16-F10 tumors from nonobese males (left) and obese males (right) (n = 3/group). Red circles and green circles represent differentially expressed genes upregulated or downregulated, respectively, following anti–PD-1 treatment. The 25 most significantly differentially expressed genes are labeled. (C) Gene set enrichment analysis (GSEA) of tumors from nonobese mice (left) and obese mice (right) showing all the gene sets significantly enriched in isotype- or anti–PD-1–treated mice (n = 3/group). (D) Tumor infiltration of CD3+ T cells and gp100-specific CD8+ T cells, measured by flow cytometry (n = 6–10/group). Unpaired 2-tailed Student’s t test was used. *P < 0.05, **P < 0.01. NES, normalized enrichment score.