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Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells

Open access
Kawalekar, Omkar U., O’Connor, Roddy S., Fraietta, Joseph A., Guo, Lili, McGettigan, Shannon E., Posey, Avery D., Patel, Prachi R., Guedan, Sonia, Scholler, John, Keith, Brian, Snyder, Nathaniel W., Blair, Ian A., Milone, Michael C., June, Carl H.·2016·Immunity
DOI 10.1016/j.immuni.2016.01.021
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Abstract

SUMMARY Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4–1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4–1BB in the CAR architecture promoted the outgrowth of CD8+ central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4–1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.

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Metadata

Authors
Kawalekar, O. U., O’Connor, R. S., Fraietta, J. A., Guo, L., McGettigan, S. E., Posey, A. D., Patel, P. R., Guedan, S., Scholler, J., Keith, B., Snyder, N. W., Blair, I. A., Milone, M. C., & June, C. H.
Venue
Immunity
Publisher
Elsevier BV
Published
2016-02
Volume
44
Issue
2
Pages
380-390
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2016.01.021
OpenAlex
W2285239684
Cited by
1,230
References
17
FWCI
39.87
Type
journal article
Language
en
Update notices
erratum (2016-03-15)
Open access
bronze
Licence

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CoChat. (2026). Citation check: Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. https://app.cochat.ai/papers/10.1016/j.immuni.2016.01.021
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Kawalekar, O. U., O’Connor, R. S., Fraietta, J. A., Guo, L., McGettigan, S. E., Posey, A. D., Patel, P. R., Guedan, S., Scholler, J., Keith, B., Snyder, N. W., Blair, I. A., Milone, M. C., & June, C. H. (2016). Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. https://doi.org/10.1016/j.immuni.2016.01.021

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.