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SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors

Cellular & Molecular Immunology volume 21, pages 213–226 (2024)Cite this article

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Abstract

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-β promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-β signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-β receptor I and abrogated the interplay between the TGF-β and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.

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Acknowledgements

This work was financially supported by a grant from the National Natural Science Foundation of China (No. 81972870), the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University (CBSKL2022ZZ20), Shaanxi Innovative Research Team for Key Science and Technology (S2022-ZC-TD-0065), the Natural Science Foundation of Henan Province (No. 222300420264), and Tangdu Hospital-key research project (2022TDGS007).

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Author notes

  1. These authors contributed equally: Sixin Liang, Rui Zheng, Baile Zuo, Jia Li.

Authors and Affiliations

  1. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Sixin Liang, Rui Zheng, Baile Zuo, Yiyi Wang, Yujie Han, Hao Dong, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Lintao Jia & Bo Yan

  2. School of Medicine Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China

    Sixin Liang, Baile Zuo, Yujie Han & Hao Dong

  3. Department of Obstetrics and Gynecology, Xijing Hospital of Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Jia Li

  4. College of Life Science, Yan’an University, Yan’an, Shaanxi, 716000, China

    Ruotong Meng

  5. Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Angang Yang

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Contributions

BLZ, BY and AGY conceived the study; BY and SXL designed the project and wrote the manuscript with inputs from SXL and RZ; BLZ, LTJ and BY provided the funding support; SXL, RZ, JL and YYW performed the majority of the experiments and data analysis; YJH, HD, XJZ, YTZ, PJW and RTM performed some of the experiments and contributed reagents, materials, and analysis tools; LTJ, AGY and BY revised the manuscript.

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Correspondence to Lintao Jia, Angang Yang or Bo Yan.

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Liang, S., Zheng, R., Zuo, B. et al. SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors. Cell Mol Immunol 21, 213–226 (2024). https://doi.org/10.1038/s41423-023-01120-y

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