Abstract
Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are applied by immune cells, resulting in the competition between conventional T cells, or indeed chimeric antigen receptor (CAR) T cells and tumor cells, for the limited availability of amino acids within the environment. We demonstrate that T cells can be re-engineered to express SLC7A5 or SLC7A11 transmembrane amino acid transporters alongside CARs. Transporter modifications increase CAR T-cell proliferation under low tryptophan or cystine conditions with no loss of CAR cytotoxicity or increased exhaustion. Transcriptomic and phenotypic analysis reveals that downstream, SLC7A5/SLC7A11-modified CAR T cells upregulate intracellular arginase expression and activity. In turn, we engineer and phenotype a further generation of CAR T cells that express functional arginase 1/arginase 2 enzymes and have enhanced CAR T-cell proliferation and antitumor activity. Thus, CAR T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognized but unaddressed barrier for successful CAR T-cell therapy.
Original language | English |
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Pages (from-to) | 1754-1761 |
Number of pages | 8 |
Journal | Blood Advances |
Volume | 7 |
Issue number | 9 |
Early online date | 15 Dec 2022 |
DOIs | |
Publication status | Published - 9 May 2023 |
Bibliographical note
Acknowledgments:The authors thank the patients and parents who contributed samples to the study.
This work was supported by Cancer Research United Kingdom (C17422/A25154) and CRUK Technologies awards, Medical Research Council's Confidence in Concept award, Takeda COCKPI-T Program, Little Princess Trust, Treating Children with Cancer, Birmingham Children’s Hospital Research Fund/Carter the Brave, the Martin family, and the alumni and donors to the University of Birmingham. The authors acknowledge the support and resources of the Birmingham Metabolic Tracer Analysis Core and Cancer Research UK Award C42109/A26982.
Copyright:
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Keywords
- Humans
- T-Lymphocytes
- Receptors, Chimeric Antigen/metabolism
- Receptors, Antigen, T-Cell/genetics
- Arginase/genetics
- Large Neutral Amino Acid-Transporter 1/metabolism
- Neoplasms/metabolism
- Amino Acids/metabolism
- Tumor Microenvironment