{"title":"用于体内肿瘤靶向 NK 细胞工程的嵌合抗原细胞毒性受体","authors":"Neha Diwanji, Daniel Getts, Yuxiao Wang","doi":"10.4049/immunohorizons.2300099","DOIUrl":null,"url":null,"abstract":"<p><p>Chimeric Ag receptor (CAR) NK cells are challenging to manufacture and fail to achieve consistent tumor infiltration and sustained cytolytic function in the tumor microenvironment. In vivo engineering of NK cells using mRNA-based CAR delivery may overcome these issues. In this study, we developed an in vivo programming method by designing CARs that leverage the biology of NK cell receptors for cell type-specific expression and function. These CARs were engineered by fusion of a tumor recognition domain with the natural cytotoxic receptor family including NKp30, NKp44, and NKp46. Our results demonstrated that these natural cytotoxic receptor-based CARs can engage endogenous signaling adaptors to effectively activate human NK cells for tumor lysis and cytokine production. Specifically, we discovered that stable expression of an NKp44-based CAR was contingent on the presence of the immune cell-specific signaling adaptor DAP12. This innovative strategy facilitates direct in situ programming of NK cells, enhancing safety and minimizing off-target effects in nontargeted, healthy tissues.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835668/pdf/","citationCount":"0","resultStr":"{\"title\":\"Chimeric Antigen Cytotoxic Receptors for In Vivo Engineering of Tumor-Targeting NK Cells.\",\"authors\":\"Neha Diwanji, Daniel Getts, Yuxiao Wang\",\"doi\":\"10.4049/immunohorizons.2300099\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Chimeric Ag receptor (CAR) NK cells are challenging to manufacture and fail to achieve consistent tumor infiltration and sustained cytolytic function in the tumor microenvironment. In vivo engineering of NK cells using mRNA-based CAR delivery may overcome these issues. In this study, we developed an in vivo programming method by designing CARs that leverage the biology of NK cell receptors for cell type-specific expression and function. These CARs were engineered by fusion of a tumor recognition domain with the natural cytotoxic receptor family including NKp30, NKp44, and NKp46. Our results demonstrated that these natural cytotoxic receptor-based CARs can engage endogenous signaling adaptors to effectively activate human NK cells for tumor lysis and cytokine production. Specifically, we discovered that stable expression of an NKp44-based CAR was contingent on the presence of the immune cell-specific signaling adaptor DAP12. This innovative strategy facilitates direct in situ programming of NK cells, enhancing safety and minimizing off-target effects in nontargeted, healthy tissues.</p>\",\"PeriodicalId\":94037,\"journal\":{\"name\":\"ImmunoHorizons\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10835668/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ImmunoHorizons\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.4049/immunohorizons.2300099\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoHorizons","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4049/immunohorizons.2300099","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
摘要
嵌合Ag受体(CAR)NK细胞的制造具有挑战性,无法在肿瘤微环境中实现稳定的肿瘤浸润和持续的细胞溶解功能。利用基于 mRNA 的 CAR 递送技术对 NK 细胞进行体内工程设计可能会克服这些问题。在这项研究中,我们开发了一种体内编程方法,通过设计 CAR,利用 NK 细胞受体的生物学特性实现细胞类型特异性表达和功能。这些 CARs 是通过将肿瘤识别域与天然细胞毒性受体家族(包括 NKp30、NKp44 和 NKp46)融合而设计的。我们的研究结果表明,这些基于天然细胞毒性受体的CAR能与内源性信号适配器结合,有效激活人类NK细胞,使其溶解肿瘤并产生细胞因子。具体来说,我们发现基于 NKp44 的 CAR 的稳定表达取决于免疫细胞特异性信号适配体 DAP12 的存在。这种创新策略有助于直接对 NK 细胞进行原位编程,提高了安全性,并最大限度地减少了对非靶向健康组织的脱靶效应。
Chimeric Antigen Cytotoxic Receptors for In Vivo Engineering of Tumor-Targeting NK Cells.
Chimeric Ag receptor (CAR) NK cells are challenging to manufacture and fail to achieve consistent tumor infiltration and sustained cytolytic function in the tumor microenvironment. In vivo engineering of NK cells using mRNA-based CAR delivery may overcome these issues. In this study, we developed an in vivo programming method by designing CARs that leverage the biology of NK cell receptors for cell type-specific expression and function. These CARs were engineered by fusion of a tumor recognition domain with the natural cytotoxic receptor family including NKp30, NKp44, and NKp46. Our results demonstrated that these natural cytotoxic receptor-based CARs can engage endogenous signaling adaptors to effectively activate human NK cells for tumor lysis and cytokine production. Specifically, we discovered that stable expression of an NKp44-based CAR was contingent on the presence of the immune cell-specific signaling adaptor DAP12. This innovative strategy facilitates direct in situ programming of NK cells, enhancing safety and minimizing off-target effects in nontargeted, healthy tissues.