美国宾夕法尼亚大学Andy J. Minn和Carl H. June课题组合作揭示了免疫刺激RNA RN7SL1使嵌合抗原受体 (CAR)-T细胞增强自主和内源性免疫功能。相关论文发表在2021年8月30日出版的《细胞》杂志上。
他们设计 CAR-T 细胞以传递 RN7SL1，这是一种内源性 RNA，可激活 RIG-I / MDA5 信号传导。RN7SL1 促进 CAR-T 细胞的扩增和效应记忆分化。此外，RN7SL1 被部署在细胞外囊泡中并选择性地转移到免疫细胞。与其他 RNA 激动剂不同，转移的 RN7SL1 限制了骨髓源性抑制细胞 (MDSC) 的发育，减少了骨髓细胞中的 TGFB，并促进了具有共刺激特征的树突状细胞 (DC) 亚群。因此，内源性效应记忆和肿瘤特异性 T 细胞也会扩增，从而排斥具有 CAR 抗原丢失的实体瘤。
在改善的内源性免疫的支持下，CAR-T 细胞现在可以与 RN7SL1 共同部署肽抗原以提高疗效，即使在异源 CAR 抗原肿瘤缺乏足够的新抗原时也是如此。
据了解，肿瘤浸润不良、衰竭进展和抗原不足是限制CAR-T 细胞功效的常见机制。递送模式识别受体激动剂是改善免疫功能的一种策略；然而，将这些激动剂靶向免疫细胞具有挑战性，并且癌细胞中的脱靶信号可能是有害的。
附：英文原文
Title: The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function
Author: Lexus R. Johnson, Daniel Y. Lee, Jacqueline S. Eacret, Darwin Ye, Carl H. June, Andy J. Minn
Issue&Volume: 2021-08-30
Abstract: Poor tumor infiltration, development of exhaustion, and antigen insufficiency arecommon mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Deliveryof pattern recognition receptor agonists is one strategy to improve immune function;however, targeting these agonists to immune cells is challenging, and off-target signalingin cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1,an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion andeffector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellularvesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferredRN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFBin myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features.Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowingrejection of solid tumors with CAR antigen loss. Supported by improved endogenousimmunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy,even when heterogenous CAR antigen tumors lack adequate neoantigens.
DOI: 10.1016/j.cell.2021.08.004
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00946-6