Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-κB Activation in T Cells and Suppressing Anti-Tumor Immunity.

Sex is known to be an important factor in the incidence, progression, and outcome of cancer. A better understand of the underlying mechanisms could help improve cancer prevention and treatment. Here, we demonstrated a crucial role of antitumor immunity in the sex differences in cancer. Consistent with observations in human cancers, male mice showed accelerated tumor progression compared to females, but these differences were not observed in immunodeficient mice. Androgen signaling suppressed T cell immunity against cancer in males. Mechanistically, androgen-activated androgen receptor (AR) upregulated expression of USP18, which inhibited TAK1 phosphorylation and the subsequent activation of NF-κB in anti-tumor T cells. Reduction of testosterone synthesis by surgical castration or using the small molecular inhibitor abiraterone significantly enhanced the anti-tumor activity of T cells in male mice and improved the efficacy of anti-PD-1 immunotherapy. Together, this study revealed a novel mechanism contributing to sex differences in cancer. These results indicate that inhibition of androgen signaling is a promising approach to improve the efficacy of immunotherapy in males.