Harnessing arginine metabolism overcomes hyperthermia-induced metabolic dysfunction of CAR T-cells
Year: 2023
Type: conference-abstract
Abstract: Chimeric antigen receptor (CAR) T-cells have shown remarkable success in the treatment of hematological malignancies, but many patients still relapse. One common adverse on-target effect of CAR T-cells is cytokine release syndrome. Importantly though, the impact of fever, a hallmark of this syndrome, on CAR T-cell function is not known. We find that exposure of CAR T-cells to hyperthermia (40°C) significantly decreased their subsequent cytotoxicity against NALM6 leukemic cells, both ex-vivo and in-vivo. This was associated with reduced secretion of IL-2, IFNg, and IL-8 by CAR T-cells and high dimensional analyses revealed the induction of a terminally differentiated T cell phenotype. Gene profiling assays highlighted a negative enrichment of mTORC1, glycolysis, and oxidative phosphorylation gene sets in CAR T-cells subjected to hyperthermia and metabolome analyses unveiled significant reductions in urea cycle metabolites. Notably, pharmacological supplementation of arginine markedly enhanced the ex-vivo and in-vivo cytotoxicity of hyperthermia-exposed CAR T-cells. Moreover, in the absence of hyperthermia, short-term arginine supplementation enhanced the metabolic fitness of CAR T-cells, augmenting their long-term in-vivo persistence and cytotoxicity. We identify arginine metabolism as a critical pathway in CAR T-cells rendered dysfunctional by exposure to hyperthermia and pharmacological arginine support will inform future iterations of CAR T-cell interventions.
Source: The Journal of Immunology
Authors: Taisuke Kondo, Justyn DuSold, Sooraj Achar, Serifat Adebola, Pedro Gonzalez-Menendez, Julie Perrault, Jennifer Jess, Bonnie Yates, Hannah Song, Stephen Fox, Xia Xu, King Chan, Abdalla Abdelmaksoud, Steven Highfill, Thorkell Andresson, Nirali Shah, Valerie Dardalhon, Grégoire Altan-Bonnet, Naomi Taylor
Institutions: National Cancer Institute, National Cancer Institute, National Cancer Institute, Center for Cancer Research, Centre National de la Recherche Scientifique, Institut de Génétique Moléculaire de Montpellier, National Institutes of Health, National Institutes of Health Clinical Center, Frederick National Laboratory for Cancer Research
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4385685776