Li JieYu, Chen LiMei, Chen MingShui, Lin Miao, Xie Zineng, Wu HuiLing, Zhou ZhiFeng, Lin WanSong
Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, PR China; Fuzhou University College of Chemistry, Fuzhou 350002, PR China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, PR China; Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, PR China.
Department of Clinical Laboratory, Fuzhou 350014, PR China.
Transl Oncol. 2025 Jul;57:102425. doi: 10.1016/j.tranon.2025.102425. Epub 2025 May 19.
Chimeric antigen receptor (CAR) T-cell immunotherapy has made significant breakthroughs in the treatment of relapsed or refractory hematologic malignancies, but its efficacy in solid tumors remains limited. In this study, we developed a chimeric NKp30 (chNKp30) receptor whose ligand, B7H6, is often up-regulated in various tumor cells and sparsely expressed in healthy cells. Introduction of the cytoplasmic structural domain of dnax-activating protein 10 (DAP10) into CAR resulted in chNKp30-Dap10 CAR-T cells that showed superior cell proliferation, activation, and apoptosis inhibition after antigenic stimulation compared with conventional chNKp30-CD28 and chNKp30-Wt CAR-T cells lacking any structural domains, along with inducing a central memory T cell phenotype, whereas chNKp30-CD28 and chNKp30-Wt triggered an effector memory phenotype. In addition, chNKp30-Dap10 T cells secreted higher levels of pro-inflammatory cytokines such as IL-2, IFN-γ, and TNF-α, while chNKp30-CD28 T cells secreted more of the anti-inflammatory cytokine IL-10. In the killing assay, chNKp30-Dap10 T cells demonstrated stronger anti-tumor effects. Similarly, better tumor regression was observed in the hepatocellular carcinoma transplantation tumor model. These findings suggest that B7H6 is an attractive therapeutic target and DAP10 signaling is involved in the functional regulation of CAR-T cells in hepatocellular carcinoma, which may induce preferential cytokine profiling and differentiation for cancer therapy, and that NKp30-Dap10 CAR-T cell therapy offers a potential option for the treatment of hepatocellular carcinoma.
嵌合抗原受体（CAR）T细胞免疫疗法在复发或难治性血液系统恶性肿瘤的治疗中取得了重大突破，但其在实体瘤中的疗效仍然有限。在本研究中，我们开发了一种嵌合NKp30（chNKp30）受体，其配体B7H6在各种肿瘤细胞中经常上调，而在健康细胞中表达稀少。将dnax激活蛋白10（DAP10）的细胞质结构域引入CAR后，产生了chNKp30-Dap10 CAR-T细胞，与缺乏任何结构域的传统chNKp30-CD28和chNKp30-Wt CAR-T细胞相比，抗原刺激后，chNKp30-Dap10 CAR-T细胞表现出更强的细胞增殖、活化和凋亡抑制能力，同时诱导了中央记忆T细胞表型，而chNKp30-CD28和chNKp30-Wt则触发了效应记忆表型。此外，chNKp30-Dap10 T细胞分泌更高水平的促炎细胞因子，如IL-2、IFN-γ和TNF-α，而chNKp30-CD28 T细胞分泌更多的抗炎细胞因子IL-10。在杀伤试验中，chNKp30-Dap10 T细胞表现出更强的抗肿瘤作用。同样，在肝癌移植瘤模型中观察到了更好的肿瘤消退。这些发现表明，B7H6是一个有吸引力的治疗靶点，DAP10信号通路参与了肝癌中CAR-T细胞的功能调节，这可能诱导优先的细胞因子谱和分化以用于癌症治疗，并且NKp30-Dap10 CAR-T细胞疗法为肝癌治疗提供了一种潜在的选择。
