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  • Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Nature (2022-03-25)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Normal Rabbit IgG, Normal Rabbit IgG Polyclonal Antibody control validated for use in Immunoprecipitation & Western Blotting.
Sigma-Aldrich
ChIPAb+ Androgen Receptor- ChIP Validated Antibody and Primer Set, from rabbit, purified by affinity chromatography