Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation

• Published in: Nature metabolism Vol. 6; no. 6; p. 1143
• Main Authors: Lakhani, Aliya, Chen, Ximin, Chen, Laurence C, Hong, Mihe, Khericha, Mobina, Chen, Yu, Chen, Yvonne Y, Park, Junyoung O
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2024
• Subjects: Cell Proliferation; Glycolysis; Humans; Immunotherapy, Adoptive - methods; Lymphocyte Activation - immunology; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Rituximab - pharmacology; Single-Chain Antibodies - immunology; Single-Chain Antibodies - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 2522-5812
• DOI: 10.1038/s42255-024-01034-7

Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.