Abstract
Surgical castration synergizes with immunotherapy, but chemical castration has suppressive effects.
Major finding: Surgical castration synergizes with immunotherapy, but chemical castration has suppressive effects.
Mechanism: AR antagonists impair T cells in part through off-target effects on GABA-A receptor signaling.
Impact: Blocking androgen synthesis may synergize with immunotherapy and avoid off-target effects.
Androgen deprivation therapy (ADT) is central to prostate cancer treatment and can be performed through surgical castration (orchiectomy), or medically through combined androgen blockade (CAB) with luteinizing hormone-releasing hormone analog (LHRH-A) and androgen receptor (AR) antagonists. Orchiectomy promotes antitumor immunity, and medical castration may as well; however, the effect of CAB on immune response remains controversial. Clinical trials evaluating immunotherapy with medical castration are under way, but it is not yet clear how immunotherapy can be combined with ADT. Pu and colleagues used the Myc-CaP transplantable prostate tumor model to study the effects of ADT on immune regulation. In this model, orchiectomy induces rapid apoptosis and tumor antigen release, providing a potential immunotherapeutic window. Orchiectomy synergized with CpG, a toll-like receptor agonist that activates dendritic cells, to reduce tumor volume, whereas CAB suppressed the CpG-induced immune response and resulted in earlier relapse. Moreover, the AR antagonist flutamide alone prevented the response to CpG in an androgen-independent manner. T-cell activation was reduced in mice treated with CpG and flutamide compared with CpG alone, indicating that AR antagonists can suppress T-cell activation, and suggesting that the efficacy of prostate cancer immunotherapy might be improved by CAB therapy following immune system activation. Nonsteroidal AR antagonists, including flutamide, engage the GABA-A receptor, which is expressed on immune cells and suppresses the immune response, suggesting that the immunosuppressive effects of AR antagonism may be mediated by off-target effects on GABA-A signaling. However, abiraterone, a steroidal inhibitor of androgen synthesis, avoided the off-target effects on GABA-A receptors and enhanced the effects of CpG, extending survival and leading to near-complete tumor regression. Together, these findings indicate that AR antagonists may potentially antagonize immunotherapy and suggest that inhibition of androgen synthesis may avoid the negative effects. Further, the timing and type of ADT may be critical for improving the efficacy of combination ADT/immunotherapy strategies in cancer.
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