GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy Journal Article
| Authors: | Shi, Y.; Kotchetkov, I. S.; Dobrin, A.; Hanina, S. A.; Rajasekhar, V. K.; Healey, J. H.; Sadelain, M. |
| Article Title: | GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy |
| Abstract: | The tumor microenvironment presents many obstacles to effective chimeric antigen receptor (CAR) T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR-T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes T stem cell-like memory formation and prolongs survival. RNA sequencing of these CAR-T cells reveals that the overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR-T cells improve tumor control and response to rechallenge in an RCC patient-derived xenograft model. Furthermore, IL13Rα2-BBz CAR-T cells overexpressing GLUT1 prolong the survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR-T cells in harsh tumor environments where glucose is limiting. © 2024 The Author(s) |
| Keywords: | controlled study; leukemia; gene mutation; human cell; genetics; nonhuman; flow cytometry; cell proliferation; t lymphocyte; t-lymphocytes; quality control; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; cell death; gene overexpression; animal experiment; animal model; antineoplastic activity; cytotoxicity; tumor xenograft; drug screening; xenograft model antitumor assays; cell line, tumor; renal cell carcinoma; acute lymphoblastic leukemia; disease model; immunology; glioblastoma; tumor cell line; western blotting; cell isolation; immunoblotting; chimeric antigen receptor; precursor cell lymphoblastic leukemia-lymphoma; upregulation; fitness; disease models, animal; glucose transporter 3; oxygen consumption; transcriptome; glycolysis; therapy; adoptive immunotherapy; immunotherapy, adoptive; rna extraction; glucose transporter 1; glucose transporter type 1; tumor microenvironment; mitochondrial respiration; procedures; density gradient centrifugation; humans; human; article; rna sequencing; b cell acute lymphoblastic leukemia; chimeric antigen receptor t-cell immunotherapy; receptors, chimeric antigen; nalm-6 cell line; glut3; glycolysis, oxidative phosphorylation, metabolism; slc2a1 protein, human; h-29 cell line |
| Journal Title: | Molecular Therapy |
| Volume: | 32 |
| Issue: | 7 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-07-03 |
| Start Page: | 2393 |
| End Page: | 2405 |
| Language: | English |
| DOI: | 10.1016/j.ymthe.2024.05.006 |
| PUBMED: | 38720457 |
| PROVIDER: | scopus |
| PMCID: | PMC11286825 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Michel Sadelain -- Rajasekhar Vinagolu's first and last names are reversed on the original publication -- Source: Scopus |
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