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Inactivation of TGF-β signaling in CAR-T cells

Cellular & Molecular Immunology volume 21, pages 309–310 (2024)Cite this article

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Accumulating evidence suggests that the transforming growth factor (TGF)-β pathway might be an ideal target for optimizing chimeric antigen receptor (CAR)-T-cell therapy for solid tumors. In Cellular & Molecular Immunology, Liang et al. (2024) reported that CAR-T cells expressing SMAD7 displayed favorable antitumor efficacy and a reduced risk of systemic toxicity.

CAR-T cells have demonstrated promising efficacy in treating hematologic malignancies. However, this approach still faces multiple challenges in eliminating solid tumors. One challenge regarding CAR-T cell treatment for solid tumors is the immunosuppressive tumor microenvironment (TME), which is characterized by high levels of multiple inhibitory factors involving the second and third signals of T-cell activation. To overcome the immunosuppressive TME, one viable strategy is the removal or blockade of coinhibitory pathways, such as PD-1, on CAR-T cells to enhance CAR-T-cell responses and restore tumor-infiltrating lymphocytes (TIL) function [1]. Another approach entails enhancing the third signal of T-cell activation. This is achieved by the transgenic expression of cytokines or engineered cytokine receptors on CAR-T cells. This strategy not only enhances CAR-T-cell expansion and persistence but also bolsters their functionality within the immunosuppressive TME [2]. Another approach focuses on modulating the response of CAR-T cells to inhibitory TME cytokines, among which TGF-β is the most prominent. TGF-β is recognized as a pivotal immunosuppressive factor due to its impact on both T-cell and macrophage functions [3].

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References

  1. Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129:1039–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bell M, Gottschalk S. Engineered cytokine signaling to improve CAR T cell effector function. Front Immunol. 2021;12:684642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32:51–82.

    Article  CAS  PubMed  Google Scholar 

  4. Wieser R, Attisano L, Wrana JL, Massagué J. Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol. 1993;13:7239–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:171–81.

    Article  CAS  PubMed  Google Scholar 

  6. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7:1118–22.

    Article  CAS  PubMed  Google Scholar 

  7. Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, et al. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26:1855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Noh KE, Lee JH, Choi SY, Jung NC, Nam JH, Oh JS, et al. TGF-β/IL-7 chimeric switch receptor-expressing CAR-T cells inhibit recurrence of CD19-positive B cell lymphoma. Int J Mol Sci. 2021;22:8706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W, et al. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. 2020;5:e133977.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022;28:724–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liang, S, Zheng R, Zuo B, Li J, Wang Y, Han Y, et al. SMAD7 expression improves the persistent and safety of CAR T cells for solid tumors. Cell Mol Immunol. 2024;21:213–26.

  12. Hong S, Lim S, Li AG, Lee C, Lee YS, Lee EK, et al. Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2. Nat Immunol. 2007;8:504–13.

    Article  CAS  PubMed  Google Scholar 

  13. Li G, Liao G, Xie J, Liu B, Li X, Qiu M. Overexpression of SMAD7 improves the function of EGFR-targeted human CAR-T cells against non-small-cell lung cancer. Respirology. 2023;28:869–80.

    Article  PubMed  Google Scholar 

  14. Tu E, Chia C, Chen W, Zhang D, Park SA, Jin W, et al. T cell receptor-regulated TGF-β type I receptor expression determines T cell quiescence and activation. Immunity. 2018;48:745–59.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Changping Laboratory, Beijing, 102206, China

    Zaopeng Yang & Yang-Xin Fu

  2. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China

    Yang-Xin Fu

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  1. Zaopeng Yang
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Correspondence to Yang-Xin Fu.

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Yang, Z., Fu, YX. Inactivation of TGF-β signaling in CAR-T cells. Cell Mol Immunol 21, 309–310 (2024). https://doi.org/10.1038/s41423-023-01123-9

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  • DOI: https://doi.org/10.1038/s41423-023-01123-9

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