Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity

The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8(+) T cells exhibited impaired effector and stem cell-like properties compared with female CD8(+ )T cells. Mechanistically, androgen receptor inhibited the activity and sternness of male tumor-infiltrating CD8(+) T cells by regulating epigenetic and transcriptional differentiation programs, Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8(+) T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8(+) T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8(+) T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.

Automated summary

This study reveals the immunological mechanism underlying sexual differences in non-reproductive cancers, showing that male CD8(+) T cells have impaired effector and stem cell-like properties compared to female CD8(+) T cells. Androgen receptor inhibits the activity and sternness of male tumor-infiltrating CD8(+) T cells, while castration combined with anti-PD-L1 treatment restricts tumor growth in male mice. In humans, male CD8(+) T cells have fewer stem cell-like memory cells, and AR expression correlates with CD8(+) T cell exhaustion in cancer patients. These findings provide insights into sex-based immunotherapeutic strategies for cancer treatment.