Recent clinical studies suggest that obese cancer patients, especially men, have a better outcome when treated with immune checkpoint inhibitors (ICI) compared to non-obese patients. However, whether obesity and sex are determinant factors influencing the antitumor immune response in the context of ICI is unknown. We hypothesized that the estrogen/androgen balance may play a role in the response to ICI as their level is known to be sex- and BMI-dependent.
Male and female mice fed with a high-fat diet to induce obesity or with a control diet were subcutaneously injected with B16-F10 melanoma cells. Obese males were treated with the aromatase inhibitor letrozole in order to decrease the estrogen/androgen ratio. ICI efficacy was assessed upon anti-PD-1 treatment by measuring tumor growth and immune cell activation markers using FACS and RNA sequencing analyses. The direct effect of sex hormones on the anti-tumor immunity was tested in vitro using murine bone marrow-derived dendritic cells and CD8+ T cells.
In non-obese mice, ICI decreased tumor growth in females but not in males. In obese mice, males and females showed the similar response to non-obese female to ICI treatment indicating that obesity sensitized to ICI in male mice only. Tumor gene expression analyses prior to ICI therapy revealed that obesity induced a female-like tumor gene expression profile in males characterized by the enrichment of differentially expressed genes involved in response to estrogen signaling. Treatment with letrozole abolished the efficacy of ICI in obese males, demonstrating the pivotal role of estrogens in the ICI sensitivity of obese males. In vitro experiments demonstrated that estrogen treatment enhanced the tumor immune response mainly by stimulating the antigen presentation capacity of dendritic cells.
These results demonstrate that the estrogen/androgen ratio can determine the response to ICI in obese mice and support the hypothesis that sex hormones may contribute to ICI sensitivity in obese male patients with melanoma. This concept opens the path to investigate whether serum sex hormones levels could be used as biomarkers for response to ICI and whether targeting the hormonal balance may be a relevant therapeutic strategy to improve the response to ICI.
The authors.
Ligue suisse contre le cancer.
All authors have declared no conflicts of interest.