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bioRxiv · 10.1101/2023.04.03.533021

Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation

Lakhani, A.·Chen, X.·Chen, L. C.·Khericha-Gandhi, M.·Chen, Y. Y.·Park, J. O.
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Abstract

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 comprised of extracellular domains that determine cancer specificity, often using single-chain variable fragments (scFvs), and intracellular domains that trigger signaling upon antigen binding. Here we show that CARs differing only in the scFv reprogram T-cell metabolism differently. Even in the absence of antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observe basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harboring 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. Since CAR-dependent metabolic reprogramming alters cellular energetics, nutrient utilization, and proliferation, metabolic profiling should be an integral part of CAR-T cell development.

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Lakhani, A., Chen, X., Chen, L. C., Khericha-Gandhi, M., Chen, Y. Y., Park, J. O.. 2023-04-04. Extracellular Domains of CAR Reprogram T-Cell Metabolism Without Antigen Stimulation. https://doi.org/10.1101/2023.04.03.533021

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