肿瘤细胞治疗研究
英文原题：Chimeric Antigen Cytotoxic Receptors for In Vivo Engineering of Tumor-Targeting NK Cells.
Chimeric Antigen Cytotoxic Receptors for In Vivo Engineering of Tumor-Targeting NK Cells.
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嵌合抗原受体（CAR）NK 细胞的制备具有挑战性，且难以在肿瘤微环境中实现一致的肿瘤浸润和持续的细胞溶解功能。
嵌合抗原受体（CAR）NK细胞的制造具有挑战性，且难以在肿瘤微环境中实现一致的肿瘤浸润和持续的细胞溶解功能。使用基于mRNA的CAR递送进行NK细胞的体内工程化可能克服这些问题。在本研究中，我们通过设计利用NK细胞受体生物学特性以实现细胞类型特异性表达和功能的CAR，开发了一种体内编程方法。这些CAR通过将肿瘤识别结构域与天然细胞毒性受体家族（包括NKp30、NKp44和NKp46）融合而工程化。我们的结果表明，这些基于天然细胞毒性受体的CAR能够接合内源性信号衔接蛋白，有效激活人NK细胞以进行肿瘤裂解和细胞因子产生。具体而言，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衔接蛋白DAP12的存在。这一创新策略促进了NK细胞的直接原位编程，提高了安全性并最大限度地减少了在非靶向健康组织中的脱靶效应。
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.
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