Androgen receptor (AR) activity can alter T-cell function and modulate resistance to PD-1 inhibitors.

  • Major Finding: Androgen receptor (AR) activity can alter T-cell function and modulate resistance to PD-1 inhibitors.

  • Concept: Inhibition of AR activity reduces CD8+ T-cell exhaustion and induces IFNγ production.

  • Impact: AR activity may be a biomarker to determine patients who will benefit from anti–PD-1/PD-L1 therapies.

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Evidence exists that T-cell function can be suppressed by androgens; however, the role that androgens and other sex hormones play in modulating cancer immunotherapy efficacy is currently not known. Therefore, Guan, Polesso, Wang, and colleagues sought to investigate how androgen deprivation therapy (ADT) with androgen receptor (AR) small-molecule therapy, the standard of care for incurable metastatic castration-resistant prostate cancer, can alter resistance to immunotherapies. Stratification of CD8+ T cells revealed two clusters: One (CD8 k1) had an induction in the expression of inhibitory genes, cytotoxic genes, and major histocompatibility complex class II, while the second (CD8 k2) had higher expression of heat-shock genes and genes associated with quiescence. The CD8 k1 subset was enriched in patients who responded to PD-1 blockade, and investigation into differences in gene signatures between responders and nonresponders showed that AR was among the top transcription factors found to be deactivated in responder CD8+ T cells. This suggests that CD8+ T-cell function can be altered by AR downregulation, with those who have low AR function are more likely to demonstrate a response to PD-1 inhibition. Moreover, in mouse models of prostate cancer and sarcoma, tumor progression was significantly reduced, while survival was increased in mice treated with ADT, anti–PD-L1 antibodies, and enzalutamide (to perturb AR) as compared to anti–PD-L1 or ADT plus enzalutamide alone. Mechanistically, this triple-drug combination increased the number of CD8+ tumor-infiltrating lymphocytes, increased their proliferation, and most notably increased production of effector cytokines including granzyme B, IFNγ, and TNF. AR was also shown to bind to open chromatin regions of Ifng and Gzmb, thereby regulating their expression, with the observed CD8+ responder signature being able to serve as a biomarker to determine which patients would benefit most from anti–PD-1 therapy. Thus, this study shows that AR can regulate T-cell function and IFNγ production, providing further insight into the role that sex hormones can play in modulation of immunity.

Guan X, Polesso F, Wang C, Sehrawat A, Hawkins RM, Murray SE, et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature 2022 Mar 23 [Epub ahead of print].

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