Article | Published:

Rewiring T-cell responses to soluble factors with chimeric antigen receptors

Nature Chemical Biology volume 14, pages 317324 (2018) | Download Citation

Abstract

Chimeric antigen receptor (CAR)-expressing T cells targeting surface-bound tumor antigens have yielded promising clinical outcomes, with two CD19 CAR-T cell therapies recently receiving FDA approval for the treatment of B-cell malignancies. The adoption of CARs for the recognition of soluble ligands, a distinct class of biomarkers in physiology and disease, could considerably broaden the utility of CARs in disease treatment. In this study, we demonstrate that CAR-T cells can be engineered to respond robustly to diverse soluble ligands, including the CD19 ectodomain, GFP variants, and transforming growth factor beta (TGF-β). We additionally show that CAR signaling in response to soluble ligands relies on ligand-mediated CAR dimerization and that CAR responsiveness to soluble ligands can be fine-tuned by adjusting the mechanical coupling between the CAR's ligand-binding and signaling domains. Our results support a role for mechanotransduction in CAR signaling and demonstrate an approach for systematically engineering immune-cell responses to soluble, extracellular ligands.

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Acknowledgements

This work was supported by the National Institutes of Health (DP5OD012133, grant to Y.Y.C.; F30CA183528, fellowship to Z.L.C.). We thank M. Jensen (Seattle Children's Research Institute), S. Forman (City of Hope National Medical Center), D. Kohn (University of California, Los Angeles), X. Lin (University of Texas MD Anderson Cancer Center), A. Weiss (University of California, San Francisco), and T. Yeates (University of California, Los Angeles) for materials used in this work. We also thank Y. Choi, H. Ho, and R. Smolkin for assistance and support in the lab.

Author information

Author notes

    • Michael H Lorenzini

    Present address: Kite Pharma, Santa Monica, California, USA.

Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA.

    • ZeNan L Chang
    • , Ximin Chen
    •  & Yvonne Y Chen
  2. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.

    • ZeNan L Chang
  3. Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA.

    • Michael H Lorenzini
  4. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.

    • Uyen Tran
  5. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.

    • Nathanael J Bangayan

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Contributions

Z.L.C. and Y.Y.C. designed the project, participated in data analysis throughout, and wrote the manuscript. Z.L.C., M.H.L., and Y.Y.C. edited and revised the manuscript. Z.L.C. developed the TGF-β CAR system and performed and analyzed microscopy, western blot, and computational modeling experiments. Z.L.C., M.H.L., and U.T. performed and analyzed TGF-β CAR flow cytometry, cytokine production, and cell expansion experiments. X.C. performed the CD19 CAR experiments. Z.L.C. and N.J.B. developed and tested the GFP CAR system.

Competing interests

Z.L.C. and Y.Y.C. declare competing financial interests in the form of a pending patent application whose value may be affected by the publication of this manuscript.

Corresponding author

Correspondence to Yvonne Y Chen.

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    Lack of bystander cell lysis by TGF-β CAR-T cells

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DOI

https://doi.org/10.1038/nchembio.2565

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