A new paper demonstrates that androgen deprivation therapy (ADT) using androgen receptor (AR) antagonists, such as enzalutamide, can impair the effectiveness of immunotherapy by interfering with initial T-cell activation, possibly via interaction with γ-aminobutyric acid receptor A (GABA-A). The data also show that correct sequencing of ADT and immunotherapy might be critical to achieve optimum effects of these combination strategies.

The efficacy of novel immunotherapies, such as sipuleucel-T, in combination with medical castration is being explored in clinical trials but results have been conflicting. In a new study published in Science Translational Medicine, Yang Pu and colleagues from China and the USA investigated the effects of pharmacological castration with luteinising-hormone-releasing hormone (LHRH) agonists and AR antagonists on the immune system, using a range of in vivo and ex vivo tumour and immune-cell models.

First, the researchers showed that AR antagonist treatment, but not LHRH agonist treatment or orchiectomy, suppressed antitumour immune responses in vivo, resulting in early tumour relapse. They observed that the immunosuppressive effect was AR-independent and mediated via suppression of T-cell responses. Exploring whether AR antagonists affect early or late stages of T-cell activation, the team found that the AR antagonist interfered with the initial T-cell priming stage. Hence, they speculated that the immunosuppressive effect might be avoidable by correct timing of the antitumour interventions and showed that sequential, but not simultaneous, administration of an immunotherapeutic agent and AR antagonist resulted in effective tumour growth inhibition in vivo.

Finally, the researchers investigated the mechanism underlying the immunosuppression and showed that T-cell impairment seemed to be mediated via an off-target effect of the AR antagonist on GABA-A. Furthermore, the team found that abiraterone, which interferes with androgen synthesis, did not show the immunosuppressive effects of the tested AR antagonists.

These new data clarify some aspects of the complex interaction between AR signalling and immune function and, in combination with further studies, might help in optimizing future clinical ADT–immunotherapy combination strategies.