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Androgen receptor activity in T cells limits checkpoint blockade efficacy
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Journal Article
Androgen receptor activity in T cells limits checkpoint blockade efficacy
2022
Overview
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 failed
1
–
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.
. Androgen-receptor blockade can overcome immunotherapy resistance in prostate cancer by intrinsically enhancing T cell function and IFNγ responses.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/21
/ 13/31
/ 13/51
/ 38
/ 38/15
/ 38/91
/ Androgen Antagonists - pharmacology
/ Androgen Antagonists - therapeutic use
/ Antigens
/ Biopsy
/ CD8-Positive T-Lymphocytes - immunology
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Male
/ Prostatic Neoplasms - drug therapy
/ Prostatic Neoplasms - immunology
/ Prostatic Neoplasms - metabolism
/ Receptors, Androgen - metabolism
/ Science
/ Therapy
/ Tumors
