Androgen receptor activity in T cells limits checkpoint blockade efficacy

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.