肿瘤细胞治疗研究
英文原题：Rab5 improves CAR T cell efficacy via reducing fratricide and maintaining surface CAR levels.
我们表明，持续的肿瘤暴露会导致嵌合抗原受体（CAR）T细胞（CART）的内吞活性丧失，这是由于Rab5的下调所致。
我们的研究表明，持续的肿瘤暴露会导致嵌合抗原受体（CAR）T细胞（CART）的内吞活性丧失，这是由Rab5下调所引起的。内吞活性的丧失加剧了胞啃作用的影响，即肿瘤靶抗原和CAR在恶性细胞与CART之间双向转移，从而导致CART功能障碍和自相残杀。在CART中持续表达Rab5可减少细胞表面胞啃捕获的抗原量，从而降低自相残杀，同时通过使CAR与靶标解离、将未结合的CAR回收至质膜以及限制肿瘤细胞对CAR的捕获来增强CAR的可用性。在从接受治疗患者的骨髓中分离出的BCMA-CART以及实体瘤模型中的间皮素特异性CART中，表达Rab5的CART均表现出更优的抗肿瘤活性。这些研究揭示了内吞作用与CART功能之间出人意料的关联，并提示将Rab5与CAR表达配对可能提高CART治疗的临床疗效。
We show continuous tumor exposure results in a loss of chimeric antigen receptor (CAR) T cell (CART) endocytic activity due to downregulation of Rab5. Loss of endocytic activity exacerbates the effects of trogocytosis, the bidirectional transfer of tumor target antigens and CARs between malignant cells and CARTs, resulting in CART dysfunction and fratricide. Constitutive expression of Rab5 within the CARTs reduced fratricide by reducing the amount of trogocytosed antigens on the cell surface, while simultaneously enhancing CAR availability through dissociation of CAR from target, recycling unbound CAR back to the plasma membrane, and limiting CAR capture by tumor cells. Rab5-expressing CARTs exhibited superior antitumor activity in both BCMA-CARTs isolated from the bone marrow of treated patients and mesothelin-specific CARTs in a solid tumor model. These studies uncover an unexpected relationship between endocytosis and CART function and suggest that pairing Rab5 with CAR expression could improve the clinical efficacy of CART therapy.
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