Androgens are known to dampen production of IFNγ, a cytokine that enhances the clinical response to immune checkpoint blockade therapy (for example, with an anti-PDl agent). However, the role of an drogens in immunotherapy resistance in metastatic castration-resistant prostate cancer (mCRPC) has been unclear. Now, a paper in Nature shows that the androgen receptor (AR) represses Ifng transcription in T cells. AR blockade restores the ability of CD8+ T cells to produce effector cytokines (including IFNγ), and AR blockade combined with androgen deprivation therapy (ADT) increases T cell response to PD1 inhibition and prolongs survival in mouse models of prostate cancer and sarcoma. Guan et al. analysed cells isolated from biopsy samples from eight individuals with mCRPC who were enrolled in a clinical trial of combined AR blockade (with enzalutamide) and PD1 blockade (three of the individuals responded to treatment with the PD1 inhibitor pembrolizumab during the trial, and five did not).
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