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

• DOI: 10.1016/j.immuni.2022.05.012
• Publication Date: 2022-06-13T14:51:47Z
• Authors: Chao Yang; Jingsi Jin; Yuanqin Yang; Hongxiang Sun; Lingling Wu; Mingyi Shen; Xiaochuan Hong; Wenwen Li; Lu Lu; Dongqing Cao; Xinran Wang; Jing Sun; Youqiong Ye; Bing Su; Liufu Deng
• Keywords: Male; 0301 basic medicine; Sex Characteristics; 0303 health sciences; CD8-Positive T-Lymphocytes; Mice; 03 medical and health sciences; Receptors, Androgen; Neoplasms; Tumor Microenvironment; Animals; Humans; Female; Immunotherapy

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 stemness 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.