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Translational Therapeutics

IL-24 improves efficacy of CAR-T cell therapy by targeting stemness of tumor cells

British Journal of Cancer volume 130, pages 1337–1347 (2024)Cite this article

Subjects

Abstract

Background

Cancer stem cells (CSCs) induce therapeutic resistance and may be an important barrier to cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in clinical settings. However, CAR-T cell therapy fails in a large proportion of patients, especially in those with solid tumors. It is unclear how CSCs mediate resistance to CAR-T cells, and whether CAR-T cells can more effectively eradicate CSCs.

Methods

In this study, the effect of CSCs on CAR-T cell therapy was determined using in vitro and in vivo assays. Subsequently, Interleukin-24 (IL-24) was expressed along with CAR in T cells. Further in vitro and in vivo tests were performed to determine the effects of IL-24 on CSCs and CAR-T cell therapy.

Results

IL-24 induced apoptosis in CSCs and contributed to T cell activation, differentiation, and proliferation. CAR.IL-24-T cells inhibited CSC enrichment and exhibited stronger antitumor activity in vitro and in vivo.

Conclusions

IL-24 helps eliminate CSCs and endows CAR-T cells with improved antitumor reactivity.

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Fig. 1: CAR-T cells exhibit antigen-specific cytotoxicity against tumor cells.
Fig. 2: CSCs show resistance to CAR-T cell therapy.
Fig. 3: IL-24 inhibits stemness of tumor cells and induces apoptosis.
Fig. 4: IL-24 increases T cell activation, central memory differentiation, and proliferation.
Fig. 5: CAR.IL-24-T cells exhibit enhanced antitumor activity in vitro.
Fig. 6: CAR.NKG2D.IL-24-T cells exhibit improved antitumor efficacy in vivo.
Fig. 7: CAR.IL-24-T cells cure late-stage tumors and provide long-term protection.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the patients and their families for their consent and participation in this clinical experiment.

Funding

This work was supported by grants from Ministry of Science and Technology (2022YFE0141000), National Natural Science Foundation of China (82272873, U2004115), Department of Science and Technology of Henan Province (221100310100, Z20221343036, SBGJ202101010, 201300310400), Health Commission of Henan Province (YXKC2021037), and First Affiliated Hospital of Zhengzhou University (QNCXTD2023010).

Author information

Author notes

  1. These authors contributed equally: Kai Zhang, Wenhao Hu, Feng Li.

Authors and Affiliations

  1. Biotherapy Center & Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Kai Zhang, Wenhao Hu, Feng Li, Chunli Wen, Lingxiao Zhou, Lei Zhang, Jingyao Lian, Shasha Liu, Shumin Wang & Yi Zhang

  2. State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China

    Yi Zhang

  3. School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China

    Yi Zhang

  4. Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China

    Yi Zhang

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Contributions

FL, YZ and KZ designed this work and analyzed the data; KZ, WHH and CLW assisted with or performed experiments and analyses; LZ and LXZ assisted in providing tumor samples; KZ, FL and YZ wrote the manuscript; KZ and FL assisted in revising the manuscript.

Corresponding author

Correspondence to Yi Zhang.

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The authors declare that they have no competing or other interests that may be perceived to influence the results and/or discussion reported in this paper.

Ethics approval and consent to participate

The research protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2019-KY-258), and informed consent was obtained from all participants included in the study, in agreement with the institutional guidelines.

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Zhang, K., Hu, W., Li, F. et al. IL-24 improves efficacy of CAR-T cell therapy by targeting stemness of tumor cells. Br J Cancer 130, 1337–1347 (2024). https://doi.org/10.1038/s41416-024-02601-1

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