肿瘤细胞治疗研究
英文原题：Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.
我们的研究证明了免疫检查点 TIM-3 的下调对 CAR T 细胞抗肿瘤功能的影响，为提升 CAR-T 细胞疗法在实体瘤中的效力提供了新思路。
增强嵌合抗原受体修饰T（CAR-T）细胞对实体瘤功能的策略至关重要。抑制性免疫检查点阻断可能增强CAR-T细胞功能。TIM-3是T细胞活性的重要负性调控因子，但TIM-3阻断是否会影响CAR-T细胞功能仍不清楚。在我们的研究中，我们通过双启动子慢病毒载体成功构建了TIM-3沉默的CAR-T细胞，该载体同时表达靶向TIM-3的短发夹RNA（shRNA）和识别HER2的第三代CAR。我们证明，TIM-3的下调不影响CAR-T细胞的表型。TIM-3阻断的CAR-T细胞在体外对靶细胞表现出更高的裂解细胞毒性。此外，TIM-3沉默的CAR-T细胞在小鼠异种移植模型中显示出强大的抗肿瘤活性，与标准CAR-T细胞相当。我们的研究证明了免疫检查点TIM-3下调对CAR T细胞抗肿瘤功能的影响，为提高CAR-T细胞疗法在实体瘤中的效力提供了新思路。
Strategies that enhance the function of chimeric antigen receptor-modified T (CAR-T) cells for solid tumors are critical. Inhibitory immuno-checkpoints blockade could potentially enhance CAR-T cell function. TIM-3 is an important negative regulator of T cell activity, but whether TIM-3 blockade could affect CAR-T cell function remains unclear. In our study, we successfully constructed TIM-3-silenced CAR-T cells by dual-promoter lentivirus vectors that simultaneously express the TIM-3 targeting short hairpin RNA (shRNA) and a third-generation CAR recognizing HER2. We demonstrated that down-regulation of TIM-3 did not affect the phenotype of CAR-T cells. CAR-T cells with TIM-3 blockade exhibited higher lytic cytotoxicity to target cells in vitro . Additionally, TIM-3-silenced CAR-T cells displayed robust anti-tumor activity in a murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates the effect of down-regulation of immune checkpoint TIM-3 on the anti-tumor function of CAR T cells, providing new ideas for improving the potency of CAR-T cell therapies in solid tumors.
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