Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-kB Activation in T Cells and Suppressing Antitumor Immunity

Abstract

Sex is known to be an important factor in the incidence, synthesis by surgical castration or using the small-molecular inhibprogression, and outcome of cancer. A better understanding of the itor abiraterone significantly enhanced the antitumor activity of T underlying mechanisms could help improve cancer prevention and cells in male mice and improved the efficacy of anti–PD-1 immutreatment. Here, we demonstrated a crucial role of antitumor notherapy. Together, this study revealed a novel mechanism con-immunity in the sex differences in cancer. Consistent with observatributing to sex differences in cancer. These results indicate that tions in human cancers, male mice showed accelerated tumor inhibition of androgen signaling is a promising approach to progression compared with females, but these differences were not improve the efficacy of immunotherapy in males. observed in immunodeficient mice. Androgen signaling suppressed T-cell immunity against cancer in males. Mechanistically, androSignificance: Androgen signaling induces immunosuppression gen-activated androgen receptor upregulated expression of USP18, in cancer by blocking T-cell activity through upregulation of USP18 which inhibited TAK1 phosphorylation and the subsequent acti- and subsequent inhibition of NF-kB activity, providing a targetable vation of NF-kB in antitumor T cells. Reduction of testosterone axis to improve antitumor immunity in males.