Estrogens determine the efficacy of cancer immunotherapy in obese males with melanoma
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
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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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 2

Obesity modulates estrogen signaling at the tumor site.

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Obesity modulates estrogen signaling at the tumor site. Male C57BL/6 mic...
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, and at day 16, tumors were collected and analyzed for gene expression (n = 3/group). (A) GSEA of RNA-sequencing data from B16-F10 tumors from isotype-treated mice, showing hallmarks significantly enriched in obese or nonobese males (n = 3/group). (B) GSEA plot of the Hallmark “Estrogen_Response_Late,” comparing obese males and nonobese males (n = 3/group). The list of genes is in the Supporting Data Values file. (C) Volcano plots of RNA-sequencing data from B16-F10 tumors from isotype-treated mice (n = 3/group). Red circles and green circles represent genes upregulated or downregulated, respectively, in obese compared with nonobese males. The 25 most significant genes from the core enrichment of the GSEA Hallmark “Estrogen_Response_Late” are labeled. (D) Levels of estrogens measured in the plasma of nonobese and obese males by evaluating the activity of estrogen receptor (ER) with a cell-based reporter assay (n = 9–10/group). Unpaired 2-tailed Student’s t test was used. ***P < 0.001. Data are depicted as mean ± SEM.