Sex-bias in CD8+ T-cell stemness and exhaustion in cancer

Abstract

This commentary article highlights two recently published studies, which for the first time revealed the immunological underpinnings of sex-bias in cancer incidence and mortality. These studies showed that the androgen receptor restrains anti-tumour immunity in males by repressing cytotoxic genes in CD8⁺ T cells.

Figure 1

Impact of androgen receptor (AR) signalling on the differentiation of intratumoural CD8⁺ T cells. Naïve CD8⁺ T cells upon tumour antigen encounter proliferate and differentiate into effector cells that produce IFN‐γ, TNF and GzmB. Upon prolonged antigen stimulation as in tumours, CD8⁺ T cells acquire an exhausted phenotype, marked by low expression of cytotoxic molecules and elevated expression of the inhibitor molecule PD‐1. Tumour‐reactive CD8⁺ T cells also contain stem‐like cells, which require expression of TCF1 and act as precursors for exhausted CD8⁺ T cells. AR signalling suppresses expression of TCF1 to restrain the differentiation of stem‐like CD8⁺ T cells while also repressing Ifng and Gzmb, thereby limiting the differentiation of effector T cells (in the box).