{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:17:34Z","timestamp":1793733454742,"version":"4.6.1"},"reference-count":48,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"unspecified","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["R01CA251253"],"award-info":[{"award-number":["R01CA251253"]}]},{"name":"NIH\/NCI","award":["R37CA249108"],"award-info":[{"award-number":["R37CA249108"]}]},{"name":"NCI","award":["P30CA093373"],"award-info":[{"award-number":["P30CA093373"]}]},{"name":"NIH\/NCI","award":["R01CA251253"],"award-info":[{"award-number":["R01CA251253"]}]},{"name":"NIH\/NCI","award":["R37CA249108"],"award-info":[{"award-number":["R37CA249108"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,3,31]]},"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Emerging data suggest that patients with enzalutamide-treated prostate cancer with increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 clinical trial revealed that the combination of atezolizumab (a PD-L1 inhibitor) and enzalutamide failed to extend overall survival in patients with castration-resistant prostate cancer (CRPC). However, the mechanisms underlying treatment failure remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human CRPC C4-2B cells and murine Myc-CaP cells were chronically exposed to increasing concentrations of enzalutamide and the cells resistant to enzalutamide were referred to as C4-2B MDVR and Myc-CaP MDVR, respectively. The mechanisms of action in drug-resistant prostate cancer cells were determined using RNA sequencing analyses, RNA interference, real-time PCR, western blotting, and co-culturing technologies. Myc-CaP and Myc-CaP MDVR tumors were established in syngeneic FVB mice, and tumor-infiltrating leukocytes were isolated after enzalutamide treatment. The stained immune cells were determined by flow cytometry, and the data were analyzed using FlowJo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Immune-related signaling pathways (interferon alpha\/gamma response, inflammatory response, and cell chemotaxis) were suppressed in human enzalutamide-resistant prostate cancer cells. PD-L1 was overexpressed and negatively regulated by androgen receptor signaling in resistant cells and patient with CRPC cohorts. Enzalutamide treatment decreased CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell numbers but increased monocytic myeloid-derived suppressor cell (M-MDSC) populations and PD-L1 expression within murine Myc-CaP tumors. Similarly, chemotaxis and immune response-regulating signaling pathways were suppressed, and PD-L1 expression was also increased using 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. Co-culturing bone marrow cells with Myc-CaP MDVR cells significantly promoted MDSC differentiation and shifted towards M2 macrophage skewing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study suggests that immunosuppressive signaling can be promoted directly by enzalutamide-resistant prostate cancer cells and may be a potential means by which the efficacy of immune checkpoint inhibitors in enzalutamide-resistant prostate cancer is diminished.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-006581","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T10:11:09Z","timestamp":1683281469000},"page":"e006581","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment"],"prefix":"10.1136","volume":"11","author":[{"given":"Pengfei","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy C","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Nip","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E","family":"Van Dyke","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Wu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, USA"},{"name":"University of California Davis Comprehensive Cancer Center, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"},{"name":"University of California Davis Comprehensive Cancer Center, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2793-401X","authenticated-orcid":false,"given":"William J","family":"Murphy","sequence":"additional","affiliation":[{"name":"University of California Davis Comprehensive Cancer Center, Sacramento, California, USA"},{"name":"Department of Dermatology and Department of Internal Medicine, University of California Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2452-8788","authenticated-orcid":false,"given":"Chengfei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, University of California Davis, Sacramento, California, USA"},{"name":"University of California Davis Comprehensive Cancer Center, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"2025100301430247000_11.5.e006581.1","unstructured":"Society AC . 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