Androgen receptor signaling and sex differences in anti-tumor dendritic cell function

About This Grant

PROJECT SUMMARY Sex differences in cancer have been clearly documented. In general, males have higher incidence rates and poorer outcomes compared to females. This difference is particularly pronounced in melanoma where females have a 38% survival advantage compared to males after adjusting for stage at diagnosis. Sex-based differences in immune function likely contribute to the sexual dimorphism observed in cancer. The female immune response has been characterized as more robust, mounting better responses to infection and vaccination than males. Further, androgens have been shown to be widely immunosuppressive. In multiple preclinical tumor models, including melanoma, androgen signaling through the androgen receptor (AR) has recently been shown to directly suppress anti-tumor T cell function. Notably, T cell function is only one aspect of the immune response. Conventional dendritic cells (cDCs) prime naïve T cells and serve to initiate and expand an antigen-specific, anti- tumor immune response. In melanoma, cDCs are required to generate a CD8+ T cell response against the tumor. However, how AR impacts anti-tumor function of cDCs is entirely unknown. Given the striking sexual dimorphism in immune system function and cancer, and the importance of cDCs in anti-tumor immune responses, there is a clear and urgent need to investigate the impact of AR signaling in cDCs. In preliminary studies in mice, we found that antigen-bearing cDCs from both male and female melanoma draining lymph nodes express AR. Importantly, we confirmed that human bone marrow derived cDCs (BMDCs) also express AR. To address the direct impact of AR-signaling on cDC function and anti-tumor immunity, we created a novel mouse model that specifically lacks AR in cDCs. Strikingly, these mice showed delayed melanoma tumor growth and significantly improved CD8+ T cell activation compared to AR-proficient control animals. Given our preliminary data, our central hypothesis is that cDC-intrinsic AR activity limits cDC function and impairs anti-tumor immunity. Here we propose to: i) identify the functional impact of cell-intrinsic AR signaling on cDC anti-tumor function using a novel mouse model where AR is deleted specifically in cDCs; ii) address the role AR in directly modulating expression of MHCI and use single-cell transcriptomics to elucidate the cDC-specific, AR-dependent, gene expression pathways driving immunosuppression; and iii) determine the efficacy of an AR-deficient, cDC-based, anti-cancer vaccine. We expect our work to contribute the mechanistic biology needed to understand how AR signaling in cDCs suppresses anti-tumor cDC function in males and females. This work will also provide key, preclinical, proof-of- concept data for targeting AR clinically in cDCs to improve cell-based vaccine efficacy. Broadly, these findings will improve our understanding of androgen-mediated immune modulation and support the integration of biologic sex as a variable in immunotherapeutic decisions.