Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
Nat Cancer. 2024 Nov;5(11):1607-1621. doi: 10.1038/s43018-024-00830-0. Epub 2024 Oct 1.
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.
人类自然杀伤 T（NKT）细胞被认为是实体瘤嵌合抗原受体（CAR）治疗的有前途的细胞平台。在这里，我们生成了小鼠 CAR-NKT 细胞，并将其与免疫活性小鼠中的 CAR-T 细胞进行了比较。CAR-NKT 细胞和 CAR-T 细胞在体外均显示出相似的抗肿瘤作用，但 CAR-NKT 细胞通过肿瘤微环境中 CD1d 依赖性免疫反应表现出更好的体内抗肿瘤活性。具体而言，我们表明 CAR-NKT 细胞消除了表达 CD1d 的 M2 样巨噬细胞。此外，CAR-NKT 细胞促进了针对肿瘤相关新抗原的内源性 T 细胞反应的表位扩展和激活。最后，我们观察到 CAR-NKT 细胞可以共表达 PD1 和 TIM3，并在高肿瘤负荷模型中表现出衰竭表型。PD1 阻断和疫苗接种增强了 CAR-NKT 细胞的抗肿瘤活性。总之，我们的结果表明 CAR-NKT 细胞在实体瘤中的多模式功能，进一步支持了在临床中开发 CAR-NKT 治疗的原理。
