Zheng Diwei, Qin Le, Lv Jiang, Che Meihui, He Bingjia, Zheng Yongfang, Lin Shouheng, Qi Yuekun, Li Ming, Tang Zhaoyang, Wang Bin-Chao, Wu Yi-Long, Weinkove Robert, Carson Georgia, Yao Yao, Wong Nathalie, Lau James, Thiery Jean Paul, Qin Dajiang, Pan Bin, Xu Kailin, Zhang Zhenfeng, Li Peng
China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China.
China-New Zealand Joint Laboratory on Biomedicine and Health, National Key Laboratory of Immune Response and Immunotherapy, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Cell Rep Med. 2025 Mar 18;6(3):102020. doi: 10.1016/j.xcrm.2025.102020.
Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4 T cells. Here, we demonstrate that CD4 but not CD8 anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4 T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8 T cells in vivo. Tumor-infiltrating CD4 T28zT2 T cells are enriched with TCF-1IL7R memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4 T28zT2 T cells and CD8 anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4 T cells is a promising strategy for eradicating solid tumors.
转化生长因子（TGF）-β1限制CD4 T细胞的扩增、存活和功能。在此，我们证明CD4而非CD8抗TGF-β嵌合抗原受体T细胞（T28zT2 T细胞）可部分通过分泌颗粒酶B和干扰素（IFN）-γ来抑制肿瘤生长。经TGF-β1处理的CD4 T28zT2 T细胞在外周血和肿瘤中持续存在良好，维持其线粒体形态和功能，且不会引起体内毒性。它们还能在体内改善未转导的CD8 T细胞的扩增和持久性。肿瘤浸润性CD4 T28zT2 T细胞富含TCF-1IL7R记忆样T细胞，表达NKG2D，并下调包括PD-1和LAG3在内的T细胞耗竭标志物。重要的是，CD4 T28zT2 T细胞与CD8抗磷脂酰肌醇蛋白聚糖-3（GPC3）或抗间皮素（MSLN）嵌合抗原受体T细胞联合使用在异种移植中表现出增强的抗肿瘤作用。这些发现表明，通过T28zT2在CD4 T细胞中重新连接TGF-β信号通路是根除实体瘤的一种有前景的策略。
