Advanced prostate cancer is the second leading cause of cancer-associated mortality in men with ~32,000 deaths each year. Castration-resistant prostate cancer has no cure and an overall survival of approximately 5 years. Strategies to block androgen receptor (AR) signaling form the backbone of prostate-cancer therapy and despite suppression of serum testosterone, intratumor concentrations of androgens can remain high. Blocking AR nuclear translocation and its transcriptional function delays disease progression, but not overall survival, in castration-resistant prostate cancer patients. In a paradigm-challenging clinical trial, anti-PD-1 blockade induced long-term durable responses in a subset of metastatic castration-resistant prostate cancer patients treated with the AR inhibitor, enzalutamide. Interestingly, T cells also express AR and their function can be directly modulated by changes in androgen availability. Given this and the success of this clinical trial, we asked if enzalutamide sensitized T cells to checkpoint immunotherapy. Using in vitro and in vivo assays, we reveal a direct effect of enzalutamide on T-cell proliferation and function. In a novel implantable mouse model of advanced prostate cancer, we highlight a requirement for androgen receptor blockade to sensitize prostate tumor-bearing animals to immunotherapy. Transcriptomic analysis of leukocytes from the tumor and draining lymph node revealed a small cohort of genes differentially regulated by enzalutamide that are consistent with increased sensitivity to checkpoint blockade. Perhaps most significant, in patients who responded to anti-PD-1 therapy, some of these same genes were upregulated prior to treatment, suggesting these could be a biomarker for immunotherapy sensitization in advanced prostate cancer patients. Taken together, our data suggest a novel mechanism targeting androgen receptor-mediated immune suppression to improve immunotherapy outcomes in advanced prostate cancer.
Note:This abstract was not presented at the conference.
Citation Format: Archana Sehrawat, Fanny Polesso, Christina Hipfinger, Xiangnan Guan, Zheng Xia, Julie Graff, Amy Moran. Targeting the androgen receptor to increase sensitivity to checkpoint immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A38.