Treg-γδ T cell axis determines sexual dimorphism in hepatocarcinogenesis

Sexual dimorphism in the incidence and mortality of hepatocellular carcinoma (HCC) has been observed worldwide. Sex hormones play an essential role in determining male predominance in hepatocarcinogenesis. Here we reveal significant sexual dimorphism in regulatory T cells (Tregs). Compared with HCC in female mice/patients, tumours in male mice/patients are more enriched in Tregs. The male sex hormone androgen is shown to activate the NFκB pathway and reinforce the binding of NFκB to Ccl2 promoter loci in HCC cells, thereby promoting Ccl2 production, which facilitates the intratumoral recruitment of Tregs via the Ccl2-Ccr2 axis. Additionally, Treg infiltration shapes the HCC microenvironment through the suppression of the antitumorigenic activity of γδ T cells rather than CD8⁺T cells. Moreover, intratumoral hypoxia induces the secretion of Treg-derived extracellular vesicle (EV)-S100a4, which serves as a transcriptional corepressor to impede γδ T cell activation in an epigenetic manner. Overall, these results demonstrate that sex-specific differences in Tregs from HCC are related to the ability of androgen-dependent Ccl2 secretion to enable immune evasion through the suppression of γδ T cell activity.