Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Abstract

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

• Authors: Xiangnan Guan, Fanny Polesso, Chaojie Wang, Archana Sehrawat, Reed M Hawkins, Susan E Murray, George V Thomas, Breanna Caruso, Reid F Thompson, Mary A Wood, Christina Hipfinger, Scott A Hammond, Julie N Graff, Zheng Xia, Amy E Moran
• Journal: Nature (Nature) Vol. 606 Issue 7915 Pg. 791-796 (06 2022) ISSN: 1476-4687 [Electronic] England
• PMID: 35322234 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Androgen Antagonists
• Immune Checkpoint Inhibitors
• Receptors, Androgen
• Interferon-gamma

Topics

• Androgen Antagonists (pharmacology, therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Immunotherapy
• Interferon-gamma
• Male
• Prostatic Neoplasms (drug therapy, immunology, metabolism)
• Receptors, Androgen (metabolism)
• Treatment Failure