Dupuychaffray Eloïse, Poinot Hélène, Vuilleumier Aurélie, Borgeaud Maxime, Alvarez Montserrat, Taskoparan Betül, Preynat-Seauve Olivier, Voegel Clarissa D, Marinari Eliana, Migliorini Denis, Dutoit Valérie, Bourquin Carole, Pommier Aurélien
School of Pharmaceutical Sciences, and.
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
JCI Insight. 2025 Jun 12;10(14). doi: 10.1172/jci.insight.189758. eCollection 2025 Jul 22.
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.
虽然肥胖是癌症的主要风险因素，但它也可能改善对癌症治疗的反应。在此，我们研究了肥胖对免疫检查点抑制剂（ICI）疗效的影响。在雄性小鼠中，肥胖促进肿瘤生长，但增强了对ICI的反应。这与肿瘤内免疫相关基因的高表达以及肿瘤特异性CD8 + T细胞浸润增加有关。此外，小鼠肥胖与较高的雌激素水平以及肿瘤中雌激素反应基因的富集有关，在给予芳香化酶抑制剂来曲唑（其可阻断雌激素的产生）后，抗程序性细胞死亡蛋白1（抗PD - 1）的疗效降低。从机制上讲，脂肪细胞衍生的雌激素增加了树突状细胞的抗原呈递和肿瘤特异性CD8 + T细胞的细胞毒性。最后，超重和肥胖的黑色素瘤男性对ICI反应更好，高雌激素水平与更好的反应和生存相关。我们的结果表明，雌激素可能是黑色素瘤男性患者对ICI反应的预测因素。
