Research ArticleCancer

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

Science Translational Medicine  06 Apr 2016:
Vol. 8, Issue 333, pp. 333ra47
DOI: 10.1126/scitranslmed.aad5659

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A winning combination

Promising results for cancer immunotherapy in the clinic have led to attempts to combine immunotherapy with standard-of-care therapies, such as androgen deprivation therapy (ADT) for prostate cancer. Now, Pu et al. report that although surgical ADT synergizes with immunotherapy to treat cancer, medical ADT may actually suppress adaptive immune responses and block the efficacy of immunotherapy. However, surgical ADT is irreversible, with ethical, psychological, and surgical concerns. The authors therefore characterized the mechanism of the immunosuppression and found that medical ADT interfered with initial T cell priming rather than reactivation and expansion. These data suggest that careful regulation of timing and dose could improve the efficacy of this combination therapy.

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.

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