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

Autor:	Panetti S; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., McJannett N; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Fultang L; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Booth S; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Gneo L; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Scarpa U; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Smith C; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Vardon A; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Vettore L; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Whalley C; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Pan Y; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Várnai C; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Endou H; J-Pharma Co. Ltd, Yokohama, Kanagawa, Japan., Barlow J; School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom., Tennant D; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Beggs A; Institute of Cancer and Genomics, University of Birmingham, Birmingham, United Kingdom., Mussai F; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., De Santo C; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2023 May 09; Vol. 7 (9), pp. 1754-1761.
DOI:	10.1182/bloodadvances.2022008272
Abstrakt:	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. (© 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.)
Databáze:	MEDLINE
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