{"title":"肿瘤 ABCC4 介导的 PGE2 释放会诱导 CD8+ T 细胞功能障碍,并损害前列腺癌的 PD-1 阻断作用。","authors":"Le Li, Zheng Chao, Hao Peng, Zhiquan Hu, Zhihua Wang, Xing Zeng","doi":"10.7150/ijbs.99716","DOIUrl":null,"url":null,"abstract":"<p><p>Prostate cancer presents as an immunologically \"cold\" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8<sup>+</sup> T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8<sup>+</sup> T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8<sup>+</sup> T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380449/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor ABCC4-mediated release of PGE2 induces CD8<sup>+</sup> T cell dysfunction and impairs PD-1 blockade in prostate cancer.\",\"authors\":\"Le Li, Zheng Chao, Hao Peng, Zhiquan Hu, Zhihua Wang, Xing Zeng\",\"doi\":\"10.7150/ijbs.99716\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Prostate cancer presents as an immunologically \\\"cold\\\" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8<sup>+</sup> T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8<sup>+</sup> T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8<sup>+</sup> T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.</p>\",\"PeriodicalId\":13762,\"journal\":{\"name\":\"International Journal of Biological Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-08-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380449/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biological Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.7150/ijbs.99716\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.99716","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
前列腺癌是一种免疫 "冷 "恶性肿瘤,大多数患者对免疫疗法缺乏反应。前列腺肿瘤代谢功能障碍被认为是免疫逃避的关键因素,导致免疫治疗干预效果降低。尽管认识到了这一点,但前列腺癌代谢失调的确切分子机制及其与免疫逃避的复杂关系仍未完全阐明。在这项研究中,我们介绍了多重耐药蛋白 ABCC4/MRP4,它是在前列腺癌中显著表达的一个关键因子,在抑制瘤内 CD8+ T 细胞活性方面发挥着关键作用。消耗前列腺癌细胞中的 ABCC4 可阻止前列腺素 E2(PGE2)的释放,而 PGE2 是一种可减少 CD8+ T 细胞数量并削弱其细胞毒性能力的分子。相反,限制 CD8+ T 细胞中 PGE2 信号的激活,能有效提高 PD-1 阻断治疗前列腺癌的疗效。在这一过程中,JAK1-STAT3通路的下调和线粒体的去极化成为导致T细胞过敏的关键因素。总之,我们的研究发现 ABCC4-PGE2 轴是扭转肿瘤浸润淋巴细胞(TILs)功能障碍和增强前列腺癌免疫疗法次优反应性的一个有希望的靶点。
Tumor ABCC4-mediated release of PGE2 induces CD8+ T cell dysfunction and impairs PD-1 blockade in prostate cancer.
Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.
期刊介绍:
The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.