{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T06:01:13Z","timestamp":1774677673875,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272840"],"award-info":[{"award-number":["82272840"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81402509"],"award-info":[{"award-number":["81402509"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021A1515010129"],"award-info":[{"award-number":["2021A1515010129"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023A1515012925"],"award-info":[{"award-number":["2023A1515012925"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021A1515010887"],"award-info":[{"award-number":["2021A1515010887"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["82272840"],"award-info":[{"award-number":["82272840"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["81402509"],"award-info":[{"award-number":["81402509"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515010129"],"award-info":[{"award-number":["2021A1515010129"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515012925"],"award-info":[{"award-number":["2023A1515012925"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515010887"],"award-info":[{"award-number":["2021A1515010887"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Metastatic prostate cancer (PCa) remains incurable and causes considerably diminished overall survival. Despite significant progress in pharmacotherapy, the disease prognosis remains unchanged. Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness in treating various advanced malignancies, but their efficacy in metastatic PCa is relatively limited. Previous studies have confirmed the immunosuppressive role of tumor-infiltrating B cells (TIL-Bs) in the PCa microenvironment, which accounts for their poor immunogenic potency. In this study, we demonstrated that an oral kinase agent, ibrutinib, strongly potentiated anti-PD-1 checkpoint blockade efficacy and successfully controlled tumor growth in a murine orthotopic PCa model constructed using a metastatic and hormone-independent cell line (RM-1). We identified close relationships between TIL-Bs, Bruton\u2019s tyrosine kinase (BTK), and immunosuppressive molecules by bioinformatics and histological analysis. An in vitro study showed that a low dose of ibrutinib significantly inhibited B cell proliferation and activation as well as IL-10 production through the BTK pathway. Moreover, ibrutinib-treated B cells promoted CD8+ T cell proliferation and inhibitory receptor (IR) expression. However, the same dose of ibrutinib was insufficient to induce apoptosis in cancer cells. An in vivo study showed that ibrutinib monotherapy failed to achieve tumor regression in murine models but decreased B cell infiltration and inhibited activation and IL-10 production. More importantly, CD8+ T cell infiltration increased with high IR expression. Ibrutinib synergized with anti-PD-1 checkpoint blockade enormously improved antitumor immunity, thereby reducing tumor volume in the same scenario. These data set the scene for the clinical development of ibrutinib as an immunogenic trigger to potentiate anti-PD-1 checkpoint blockade for metastatic PCa immunotherapy.<\/jats:p>","DOI":"10.3390\/cancers15082356","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T01:09:22Z","timestamp":1681866562000},"page":"2356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ibrutinib Inhibits BTK Signaling in Tumor-Infiltrated B Cells and Amplifies Antitumor Immunity by PD-1 Checkpoint Blockade for Metastatic Prostate Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Gengguo","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiannan","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qunxiong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tengcheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhansen","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuntian","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinbin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiantian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinming","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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