Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

Sci Transl Med. 2016 Apr 6;8(333):333ra47. doi: 10.1126/scitranslmed.aad5659.

Abstract

Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with γ-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Immunity / drug effects
  • Immunotherapy
  • Lymphocyte Activation / drug effects
  • Male
  • Mice, Inbred C57BL
  • Neoplasm Recurrence, Local / pathology*
  • Orchiectomy
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / surgery
  • Receptors, Androgen / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Androgen Receptor Antagonists
  • Receptors, Androgen
  • gamma-Aminobutyric Acid