{"title":"经改造可分泌 IFN-κ 的 CAR T 细胞通过 IFNAR/STAT1/ACSL4 轴诱导肿瘤铁变态反应。","authors":"Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang","doi":"10.1158/2326-6066.CIR-24-0130","DOIUrl":null,"url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.\",\"authors\":\"Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang\",\"doi\":\"10.1158/2326-6066.CIR-24-0130\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.</p>\",\"PeriodicalId\":9474,\"journal\":{\"name\":\"Cancer immunology research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer immunology research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/2326-6066.CIR-24-0130\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer immunology research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2326-6066.CIR-24-0130","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
铁突变是一种影响癌症免疫的铁依赖性细胞死亡形式。对铁凋亡的治疗调节被认为是提高其他癌症疗法疗效的一种潜在策略,包括嵌合抗原受体(CAR)T细胞疗法等免疫疗法。在这项研究中,我们证明了 IFN-κ 对铁卟啉诱导的影响。IFN-κ能增强肿瘤细胞对小分子化合物麦拉宁和多不饱和脂肪酸花生四烯酸诱导的铁变态反应的敏感性。从机理上讲,IFN-κ与花生四烯酸结合可通过IFNAR/STAT1/ACSL4轴诱导免疫原性肿瘤铁中毒。此外,表达 IFN-κ 的 CAR T 细胞在体外和体内对 H460 细胞(抗原阳性)和 H322 细胞(抗原阴性)的抗肿瘤效率都有所提高。我们的结论是,IFN-κ是一种潜在的细胞因子,可以通过诱导肿瘤铁变态反应来增强CAR T细胞的抗肿瘤功能。
CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.
Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.