Androgen receptor activity in T cells limits checkpoint blockade efficacy

Nature. 2022 Jun;606(7915):791-796. doi: 10.1038/s41586-022-04522-6. Epub 2022 Mar 23.


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.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use
  • CD8-Positive T-Lymphocytes* / immunology
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy*
  • Interferon-gamma
  • Male
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / immunology
  • Prostatic Neoplasms* / metabolism
  • Receptors, Androgen* / metabolism
  • Treatment Failure


  • Androgen Antagonists
  • Immune Checkpoint Inhibitors
  • Receptors, Androgen
  • Interferon-gamma