Androgen receptor activity in T cells limits checkpoint blockade efficacy

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 and Amy E. Moran ()
Additional contact information
Xiangnan Guan: Oregon Health and Science University
Fanny Polesso: Oregon Health and Science University
Chaojie Wang: Oregon Health and Science University
Archana Sehrawat: Oregon Health and Science University
Reed M. Hawkins: Oregon Health and Science University
Susan E. Murray: Oregon Health and Science University
George V. Thomas: Oregon Health and Science University
Breanna Caruso: Oregon Health and Science University
Reid F. Thompson: Oregon Health and Science University
Mary A. Wood: VA Portland Health Care System
Christina Hipfinger: Oregon Health and Science University
Scott A. Hammond: AstraZeneca
Julie N. Graff: Oregon Health and Science University
Zheng Xia: Oregon Health and Science University
Amy E. Moran: Oregon Health and Science University

Nature, 2022, vol. 606, issue 7915, 791-796

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04522-6

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