Engineering amino acid uptake or catabolism promotes CAR T-cell adaption to the tumor environment

Silvia Panetti, Nicola Jane McJannett, Livingstone Fultang, Sarah Booth, Luciana Gneo, Ugo Scarpa, Charles Smith, Ashley Vardon, Lisa Vettore, Celina Whalley, Yi Pan, Csilla Varnai, Hitoshi Endou, Jonathan Barlow, Daniel A. Tennant, Andrew D. Beggs, Francis Jay Mussai*, Carmela De Santo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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 languageEnglish
Pages (from-to)1754-1761
Number of pages8
JournalBlood Advances
Volume7
Issue number9
Early online date15 Dec 2022
DOIs
Publication statusPublished - 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

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