Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer
Menée in vitro et à l'aide de modèles murins de cancer de la vessie, cette étude met en évidence un mécanisme par lequel les androgènes, en induisant le dysfonctionnement des lymphocytes T CD8+, rendent les tumeurs plus agressives et affectent l'efficacité des immunothérapies anti-PD1
Sex bias exists in the development and progression of non-reproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent anti-tumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional trans-activator of Tcf7/TCF1. The T cell intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.
Science Immunology , résumé, 2021