Mp20-11 enzalutamide resistance results in immunosuppressive alterations in prostate tumor immune microenvironment

You have accessJournal of UrologyCME1 Apr 2023MP20-11 ENZALUTAMIDE RESISTANCE RESULTS IN IMMUNOSUPPRESSIVE ALTERATIONS IN PROSTATE TUMOR IMMUNE MICROENVIRONMENT Pengfei Xu, Joy C. Yang, Bo Chen, Christopher Nip, Jonathan E Van Dyke, Christopher P. Evans, William J. Murphy, and Chengfei Liu Pengfei XuPengfei Xu More articles by this author , Joy C. YangJoy C. Yang More articles by this author , Bo ChenBo Chen More articles by this author , Christopher NipChristopher Nip More articles by this author , Jonathan E Van DykeJonathan E Van Dyke More articles by this author , Christopher P. EvansChristopher P. Evans More articles by this author , William J. MurphyWilliam J. Murphy More articles by this author , and Chengfei LiuChengfei Liu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Emerging data suggested that enzalutamide-treated prostate cancer patients with increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 trial revealed that the combination of atezolizumab (PD-L1 inhibitor) and enzalutamide failed to extend overall survival in patients with castration-resistant prostate cancer (CRPC). The mechanisms underlying treatment failure remain unknown. In this study, we investigated the regulation of immunosuppressive signaling in enzalutamide resistant prostate cancer and characterized the immune infiltrating cells in murine prostate tumors. METHODS: The expression of interferon gamma-related genes was determined using qRT-PCR and/or western blotting. Androgen receptor (AR) and AR-V7 levels were downregulated using specific siRNA. Myc-CaP cells were chronically exposed to increasing concentrations of enzalutamide (5-50 μM) for >12 months, and the cells resistant to enzalutamide were referred to as Myc-CaP MDVR. The gene-regulating mechanisms in drug-resistant prostate cancer cells were determined by RNA sequencing analyses. Myc-CaP and Myc-CaP MDVR xenograft tumors were established in FVB mice, and tumor-infiltrating lymphocytes were isolated using Ficoll. The stained immune cells were determined by flow cytometry, and the data were analyzed using Flowjo. RESULTS: Immune-related signaling pathways (interferon alpha/gamma response, T cell activation, and cell chemotaxis pathways) were suppressed in C4-2B MDVR cells (p<0.001). However, PD-L1 expression was highly upregulated and negatively regulated by AR in C4-2B MDVR cells. Enzalutamide treatment decreased CD8+ T cell (14.8% vs. 10.3%, p<0.05) but increased monocytic myeloid-derived suppressor cell (M-MDSC) population (23.0% vs. 34.2%, p<0.05) and PD-L1 expression in murine Myc-CaP tumors. Consistently, chemotaxis and immune response-regulating signaling pathways were suppressed, and PD-L1 expression was increased in enzalutamide-resistant Myc-CaP MDVR cells. Notably, MDSC populations were significantly increased in Myc-CaP MDVR orthotopic tumors compared with those in Myc-CaP parental tumors (4.0% vs. 1.6%, p<0.01). Co-culturing bone marrow cells with Myc-CaP MDVR cells significantly promoted MDSC differentiation and polarized macrophages from the M1 to M2 phase. CONCLUSIONS: Immunosuppressive signaling is activated in enzalutamide resistant prostate cancer cells. The activated immune-related signatures involved in T cells, MDSC, and macrophages may reduce the efficacy of immune checkpoint inhibitors in enzalutamide-resistant prostate cancer. Source of Funding: This work was supported in part by grants NIH/NCI R37CA249108 (C, Liu) and R01CA251253 (C, Liu) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e279 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pengfei Xu More articles by this author Joy C. Yang More articles by this author Bo Chen More articles by this author Christopher Nip More articles by this author Jonathan E Van Dyke More articles by this author Christopher P. Evans More articles by this author William J. Murphy More articles by this author Chengfei Liu More articles by this author Expand All Advertisement PDF downloadLoading ...