An Inhibitory Role for Human CD96 Endodomain in T Cell Anti-Tumor Responses.
An Inhibitory Role for Human CD96 Endodomain in T Cell Anti-Tumor Responses.
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作者：
免疫检查点阻断（ICB）疗法涉及免疫检查点调节剂的抑制，这逆转了它们对T细胞抗肿瘤应答的限制，并导致持久的肿瘤消退。然而，在接受这种治疗的一些患者中观察到不良临床反应或肿瘤复发，所述治疗通过单独或组合阻断细胞毒性T淋巴细胞相关蛋白4（CTLA-4）或程序性细胞死亡1（PD-1）途径的抗体施用，表明涉及额外的免疫检查点。CD 96是一种可能的免疫检查点，以前被证明可以抑制自然杀伤（NK）细胞的抗肿瘤活性，但其在人类T细胞中的作用仍然存在争议。在这里，我们证明了人类T细胞中基于CRISPR/Cas9的CD 96缺失增强了它们在体外对白血病细胞的杀伤。与携带缺乏CD 96胞内结构域的CAR的对应物（4D 5-z CAR-T细胞）相比，用包含人表皮生长因子受体2（EGFR 2/HER 2）结合胞外区和CD 96和CD 3 β的胞内区的嵌合抗原受体（CAR）工程化的T细胞（4D 5 - 96 z CAR-T细胞）在体外和体内抑制表达HER 2的肿瘤细胞的生长方面不太有效。总之，我们的发现暗示了CD 96胞内域在减弱T细胞细胞毒性中的作用，并支持靶向多个而不是单个免疫检查点的联合肿瘤免疫疗法。
Immune checkpoint blockade (ICB) therapy involves the inhibition of immune checkpoint regulators which reverses their limitation of T cell anti-tumor responses and results in long-lasting tumor regression. However, poor clinical response or tumor relapse was observed in some patients receiving such therapy administered via antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway alone or in combination, suggesting the involvement of additional immune checkpoints. CD96, a possible immune checkpoint, was previously shown to suppress natural killer (NK) cell anti-tumor activity but its role in human T cells remains controversial. Here, we demonstrate that CRISPR/Cas9-based deletion of CD96 in human T cells enhanced their killing of leukemia cells in vitro. T cells engineered with a chimeric antigen receptor (CAR) comprising human epidermal growth factor receptor 2 (EGFR2/HER2)-binding extracellular region and intracellular regions of CD96 and CD3ζ (4D5-96z CAR-T cells) were less effective in suppressing the growth of HER2-expressing tumor cells in vitro and in vivo compared with counterparts bearing CAR that lacked CD96 endodomain (4D5-z CAR-T cells). Together, our findings implicate a role for CD96 endodomain in attenuating T cell cytotoxicity and support combination tumor immunotherapy targeting multiple rather than single immune checkpoints.
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