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, Amy E. Moran

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
JournalNature
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • General

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