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Androgen receptor activity in T cells limits checkpoint blockade efficacy

Xiangnan Guan1,2,3, Fanny Polesso4, Chaojie Wang4,5

  • 1Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA.

Nature
|March 24, 2022
PubMed

Insights

Androgen receptor (AR) blockade enhances CD8 T cell function, improving immunotherapy response in prostate cancer. This approach prevents T cell exhaustion and increases anti-tumour immunity by boosting IFNγ expression.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint blockade revolutionized cancer treatment, but immunotherapy has largely failed in advanced prostate cancer.
  • Androgen deprivation therapy is standard for prostate cancer, potentially impacting anti-tumour T cells.

Purpose of the Study:

  • To investigate if androgen receptor (AR) blockade can sensitize prostate tumours to immunotherapy.
  • To elucidate the mechanism by which AR signaling affects T cell function and immunotherapy response.

Main Methods:

  • Inhibition of AR activity in CD8 T cells from tumour-bearing hosts.
  • Assessment of T cell exhaustion markers and responsiveness to PD-1 blockade.
  • Analysis of Interferon-gamma (IFNγ) expression and AR binding to the Ifng gene.

Main Results:

  • AR blockade prevented CD8 T cell exhaustion and enhanced response to PD-1 targeted therapy.
  • Inhibition of AR activity in CD8 T cells led to increased IFNγ production.
  • AR was found to directly bind to the Ifng gene, and its eviction increased CD8 T cell cytokine production.

Conclusions:

  • T cell-intrinsic AR activity suppresses IFNγ expression, representing a novel mechanism of immunotherapy resistance in prostate cancer.
  • Targeting AR in T cells can enhance immunotherapy efficacy, offering a new strategy for treating advanced prostate cancer.

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