期刊
SCIENCE IMMUNOLOGY
卷 7, 期 73, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abq2630
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类别
资金
- NIH [K08AI139375, R01 CA213290, R01 CA262069, R01 CA255334, R01 CA262338, R01 AI077283, R01 DK110477, U01 DK131377, R21 CA249701]
- Prostate Cancer Foundation
- Damon Runyon Clinical Investigator Award
- Canadian Institutes of Health Research [201810DFS-422133-63414]
- Hollings Cancer Center in Charleston, SC, USA
- Ohio State University Comprehensive Cancer Center's Tumor Immunology T32 postdoctoral fellowship award [2T32CA09223-16A1]
This study reveals a sex bias in the development and progression of nonreproductive organ cancers, with male patients having a higher frequency of CD8(+) T cells lacking effector activity. This bias is driven by gonadal androgen and not by sex chromosomes. The androgen receptor plays a crucial role in promoting CD8(+) T cell exhaustion through a sex-specific regulon and acts as a direct transcriptional transactivator of Tcf7/TCF1. Inhibiting the androgen receptor rewires the tumor microenvironment, favoring effector T cell differentiation and enhancing the efficacy of anti-PD-1 immune checkpoint blockade.
Sex bias exists in the development and progression of nonreproductive 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 antitumor 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 transactivator 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.
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