Yang and Jin et al. demonstrated that, compared to female, male CD8+ T cells exhibited impaired effector and stem cell-like properties, leading to sex-biased antitumor immunity during cancer progression and in responses to immunotherapy. In male tumor models, androgen receptor (AR) signaling transcriptionally regulated the differentiation of stem cell-like CD8+ T cells to terminally exhausted CD8+ T cells, and ablation of AR signaling via castration enhanced the activity of tumor-reactive CD8+ T cells and the efficacy of anti-PD-L1 treatment. In human patients with cancer, AR expression correlated with tumor-infiltrating CD8+ T cell exhaustion.
Contributed by Shishir Pant
ABSTRACT: 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.