文章：

T-bet促进CD4+ CAR - T细胞有效的抗肿瘤活性

T-bet promotes potent antitumor activity of CD4+ CAR T cells

原文发布日期：2018-03-07

英文摘要：

Chimeric antigen receptor (CAR) therapy has shown promise against B cell malignancies in the clinic. However, limited success in patients with solid tumors has prompted the development of new CAR strategies. In this study, a B7H6-specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4+ T cells, to create more effective CAR T cells. Skewing CD4+ CAR T cells into a Th1 improved CAR T cell functional activity while promoting a robust proinflammatory response against B7H6-expressing tumors. The expression of T-bet with the B7H6-specific CAR in CD4+ T cells conferred higher expression of the CAR, elevated secretion of Th1 and proinflammatory cytokines, and improved cellular cytotoxicity against B7H6-expressing tumor cells. In vivo, CD4+ T cells co-expressing a B7H6-specific CAR and T-bet improved the survival of RMA-B7H6 lymphoma-bearing mice. Thus, CD4+ CAR T cells with increased T-bet expression have the potential to modify the tumor microenvironment and the immune response to better treat solid and hematologic cancers. 

摘要翻译：

嵌合抗原受体（CAR）疗法在临床上已显示出对抗B细胞恶性肿瘤的潜力，然而其在实体瘤患者中的疗效有限，这促使了新CAR策略的开发。本研究将B7H6特异性CAR与T-bet（一种作为主调控因子诱导CD4+ T细胞向Th1表型分化的转录因子）的不同变体相结合，以构建更有效的CAR T细胞。通过促使CD4+ CAR T细胞向Th1方向分化，不仅增强了CAR T细胞的功能活性，同时促进了针对B7H6表达肿瘤的强烈促炎反应。在CD4+ T细胞中共同表达B7H6特异性CAR与T-bet，可提高CAR的表达水平，增加Th1及促炎细胞因子的分泌，并增强对B7H6表达肿瘤细胞的细胞毒性。在体内实验中，共同表达B7H6特异性CAR与T-bet的CD4+ T细胞显著延长了携带RMA-B7H6淋巴瘤小鼠的生存期。因此，通过增强T-bet表达来改造CD4+ CAR T细胞，有望改变肿瘤微环境及免疫应答，从而更有效地治疗实体瘤和血液系统恶性肿瘤。

原文链接：

T-bet promotes potent antitumor activity of CD4+ CAR T cells