Zheng and Qin et al. engineered third-generation CAR T cells targeting TGFβ, and showed that CD4+, but not CD8+ anti-TGFβ CAR T cells (T28zT2 T cells) suppressed tumor growth. Tumor-infiltrating CD4+ T28zT2 T cells were enriched in a memory-like (TCF-1+IL7R+) T cell phenotype, maintained mitochondrial function, did not cause in vivo toxicity, and improved untransduced CD8+ T cell expansion and persistence in vivo. The combination of CD4+ T28zT2 T cells with CD8+ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells showed improved antitumor effects compared with conventional CD3+ CAR T cells.
Contributed by Shishir Pant
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.
Author Info: (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
Author Info: (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) 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. (4) 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. (5) Department of Radiology, Translational Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (6) 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. (7) 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. (8) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (9) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (10) Guangdong Zhaotai Cell Biology Technology Ltd., Foshan, China. (11) Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China. (12) Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China. (13) Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand. (14) Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand. (15) 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. (16) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (17) Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China. (18) Guangzhou Laboratory, Guangzhou, China. (19) The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (20) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (21) Blood Disease Institution, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China. (22) Department of Radiology, Translational Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (23) 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.
