Investigation of the impact of sex hormones on cancer immunotherapy outcome

• Applicant: Professorin Dr. Sonja Loges, since 1/2025
• Subject Area: Immunology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Sex has been shown to have a significant influence on incidence, mortality and treatment responses in cancer. Men show poorer outcomes and lower survival compared to women in most non-reproductive cancer types, but, interestingly male cancer patients respond better to immune checkpoint blockade (ICB). Both innate and adaptive immunity harbor a considerable sex bias which is understudied especially in the context of anti-cancer immune responses. In addition, androgen receptors (AR) have been detected in many different hematopoietic cells leading to direct effects of their ligands on the development and function of the immune system. In the first funding period we found that in tumor-bearing mice, anti-PD1 treatment exhibited higher efficacy in males compared to females. Remarkably, the disadvantage observed in females could be reverted with testosterone supplementation. Besides, immunophenotyping analysis showed that upon ICB males and testosterone-supplemented females had significantly increased intratumoral stem-like CD8+TCF1+PD1+ T cells compared to placebo-treated females. These results suggest that androgens can directly modulate anti-cancer immune responses by contributing to a more sustained anti-tumor CD8+ T cell response, and consequently better responses upon ICB. Moreover, these findings are in concordance with clinical data and warrant therapy escalation in female patients. During the second funding period, we propose to conduct an in-depth study of the mechanisms elicited by androgens in CD8+ T cells upon anti-PD1 blockade. Furthermore, we will investigate the influence of androgen signaling in NK- and NKT cells on responses to ICB. In addition, we plan to explore the impact of testosterone on the cellular composition of the tumor microenvironment (TME) at the single cell level to understand cellular cross-talk underlying sex-biased response to ICB. To accomplish these goals, we will utilize the in vivo models established in our laboratory in the prior funding period, along with samples obtained from lung cancer patients before and after ICB treatment. We will also perform co-cultures of T cells or NK cells together with tumor cells and conduct drug screening in 3D organoid cultures. Furthermore, we will employ single-cell multi-omics technologies. Thereby, we will gain novel functional insights into the role of AR signaling in T cells and NK cells obtaining a comprehensive immune landscape of TME heterogeneity and underlying mechanisms of sex-bias upon application of ICB. Our ultimate goal, is to pave the road for clinical trials with the aim to increase the number of patients deriving long-term benefit from ICB and possible other immune therapies.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity
• Ehemalige Antragstellerin: Isabel Ben Batalla, Ph.D., until 12/2024