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  3. CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects

CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effects

  • Cell Rep Med. 2025 Mar 18;6(3):102020. doi: 10.1016/j.xcrm.2025.102020.
Diwei Zheng 1,  Le Qin 2,  Jiang Lv 2,  Meihui Che 2,  Bingjia He 3,  Yongfang Zheng 2,  Shouheng Lin 2,  Yuekun Qi 4,  Ming Li 5,  Zhaoyang Tang 6,  Bin-Chao Wang 7,  Yi-Long Wu 7,  Robert Weinkove 8,  Georgia Carson 8,  Yao Yao 2,  Nathalie Wong 5,  James Lau 5,  Jean Paul Thiery 9,  Dajiang Qin 10,  Bin Pan 4,  Kailin Xu 4,  Zhenfeng Zhang 3,  Peng Li 11
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Radiology, Translational Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 4 Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5 Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Guangdong Zhaotai Cell Biology Technology Ltd., Foshan, China.
  • 7 Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 8 Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand.
  • 9 Guangzhou Laboratory, Guangzhou, China.
  • 10 The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 11 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. Electronic address: li_peng@gibh.ac.cn.
PMID: 40107245 DOI: 10.1016/j.xcrm.2025.102020
Abstract

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-1+IL7R+ 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.

Keywords

CAR T; SMAD4; T cell exhaustion; TGFβ1; glypican-3; mesothelin; mitochondrial fission.

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