肿瘤细胞治疗研究
英文原题：CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.
我们的结果表明 CAR-NKT 细胞在实体瘤中具有多模式功能，进一步支持在临床中开发 CAR-NKT 疗法的合理性。
人自然杀伤 T（NKT）细胞被认为是实体瘤嵌合抗原受体（CAR）治疗的一种有前景的细胞平台。本研究制备了小鼠 CAR-NKT 细胞，并在免疫功能完整的小鼠中与 CAR-T 细胞进行比较。CAR-NKT 细胞和 CAR-T 细胞在体外均显示相似的抗肿瘤作用；但在体内，CAR-NKT 细胞通过肿瘤微环境中 CD1d 依赖性免疫应答，表现出更强的抗肿瘤活性。具体而言，我们显示 CAR-NKT 细胞可清除表达 CD1d 的 M2 样巨噬细胞。此外，CAR-NKT 细胞促进表位扩展，并激活针对肿瘤相关新抗原的内源性 T 细胞应答。最后，在肿瘤负荷较高的模型中，我们观察到 CAR-NKT 细胞可共表达 PD1 和 TIM3，并呈现耗竭表型。阻断 PD1 以及接种疫苗均可增强 CAR-NKT 细胞的抗肿瘤活性。总之，我们的结果显示 CAR-NKT 细胞在实体瘤中具有多模式作用，进一步支持在临床开发 CAR-NKT 疗法的理论依据。
Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.
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