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Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors

Cellular & Molecular Immunology volume 21, pages 1491–1504 (2024)Cite this article

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Abstract

Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich 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), Tangdu Hospital-key research project (2022TDGS007).

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Author notes

  1. These authors contributed equally: Rui Zheng, Kuo Shen, Sixin Liang, Yanhong Lyu.

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, China

    Rui Zheng, Sixin Liang, Hao Dong, Yujie Han, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Shukun Bai, Jianxun Yang & Bo Yan

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

    Rui Zheng, Sixin Liang, Pengju Wang, Angang Yang & Rui Zhang

  3. Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Kuo Shen

  4. Air Force Hospital of Western Theater Command, Chengdu, Sichuan, 610065, China

    Kuo Shen

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

    Yanhong Lyu, Yuanfeng Li & Jia Li

  6. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Siyan Zhang

  7. Department of Ultrasound, The first affliated hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Siyan Zhang

  8. School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China

    Hao Dong & Yujie Han

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

    Ruotong Meng & Jianxun Yang

  10. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’ an, Shaanxi, China

    Guofang Lu

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Contributions

RZ, BY, AGY and JL conceived the idea of the study and designed experiments; RZ and BY designed the project of the study; RZ, KS, SXL and YHL performed the majority of the experiments and SYZ, HD, YJH, XJZ, YTZ, PJW, RTM and SKB performed the part of the experiments and acquired data; RZ, KS analyzed data and interpreted results; BY, JL advised on the design of human primary organoid; JL performed the surgery to obtain the tissue of ovarian cancer patients, FYL cultured the organoid and RZ, KS, YHL and SXL performed the further experiments of CAR-T; JL, RZ, KS, SXL and FYL wrote the manuscript with feedback from all authors. RZ, BY, JXY and GFL revised the manuscript. BY and AGY supervised the work.

Corresponding authors

Correspondence to Jia Li, Angang Yang, Rui Zhang or Bo Yan.

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Zheng, R., Shen, K., Liang, S. et al. Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors. Cell Mol Immunol 21, 1491–1504 (2024). https://doi.org/10.1038/s41423-024-01228-9

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