Investigating the functional effects of enhanced glucose metabolism in T cells with chimeric antigen receptors
Abstract/Contents
- Abstract
- The combination of intensive nutrient requirements needed to sustain T cell activation and proliferation, alongside competition for nutrients within the tumor microenvironment suggest that glucose availability could limit CAR T cell function. Here we sought to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve function and antitumor potency. We observed that GLUT1OE CAR T cells manifest increased glucose uptake at rest and following activation, and this is associated with increased glycolysis and oxidative phosphorylation. In addition, GLUT1OE also enhanced MTOR signaling and broadly modulated metabolic programming, with substantial increases in glutathione mediated resistance to reactive oxygen species, and enhanced urea cycle and arginine metabolism. We observed no evidence for increased T cell exhaustion with GLUT1OE, but rather observed increased TCF1+ and CD62L, consistent with stemness programming. GLUT1OE CAR T cells showed increased cytokine production in response to tumor challenge and manifested superior tumor control in vivo. Our collective findings support a model wherein glucose availability is rate limiting for optimal effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1 OE provides a new approach to augment antitumor immune function.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Arredondo-Guerrero, Justin |
|---|---|
| Degree supervisor | Mackall, Crystal |
| Thesis advisor | Mackall, Crystal |
| Thesis advisor | Bendall, Sean, 1979- |
| Thesis advisor | Bollyky, Paul |
| Thesis advisor | Majzner, Robbie |
| Thesis advisor | Meyer, Everett |
| Degree committee member | Bendall, Sean, 1979- |
| Degree committee member | Bollyky, Paul |
| Degree committee member | Majzner, Robbie |
| Degree committee member | Meyer, Everett |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Justin Arredondo-Guerrero. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/pv518bj2942 |
Access conditions
- Copyright
- © 2023 by Justin Arredondo-Guerrero
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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