Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation

Aliya Lakhani; Ximin Chen; Laurence C Chen; Mihe Hong; Mobina Khericha; Yu Chen; Yvonne Y Chen; Junyoung O Park

doi:10.1038/s42255-024-01034-7

Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation

Nat Metab. 2024 Apr 24. doi: 10.1038/s42255-024-01034-7. Online ahead of print.

Authors

Aliya Lakhani¹, Ximin Chen¹, Laurence C Chen¹, Mihe Hong¹, Mobina Khericha², Yu Chen³, Yvonne Y Chen^{1

2

4

5}, Junyoung O Park^{6

7}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA.
⁵ Parker Institute for Cancer Immunotherapy at UCLA, Los Angeles, CA, USA.
⁶ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA. jop@ucla.edu.
⁷ Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA. jop@ucla.edu.

PMID: 38658805
DOI: 10.1038/s42255-024-01034-7

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 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.

Abstract

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