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

Omkar U Kawalekar; Roddy S O'Connor; Joseph A Fraietta; Lili Guo; Shannon E McGettigan; Avery D Posey, Jr; Prachi R Patel; Sonia Guedan; John Scholler; Brian Keith; Nathaniel W Snyder; Ian A Blair; Michael C Milone; Carl H June

doi:10.1016/j.immuni.2016.01.021

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

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

Omkar U Kawalekar, Roddy S O'Connor, Joseph A Fraietta, Lili Guo, Shannon E McGettigan, Avery D Posey, Jr, Prachi R Patel, Sonia Guedan, John Scholler, Brian Keith, …

Immunity (Cambridge, Mass.), v 44(2), pp 380-390

16 Feb 2016

DOI: https://doi.org/10.1016/j.immuni.2016.01.021

PMID: 26885860

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Abstract

Cancer Vaccines - immunology

CD28 Antigens - genetics

CD28 Antigens - metabolism

CD8-Positive T-Lymphocytes - physiology

Cell Respiration

Cells, Cultured

Glycolysis

Humans

Immunologic Memory

Mitochondria - metabolism

Neoplasms - immunology

Neoplasms - therapy

Receptor Cross-Talk

Receptors, Antigen, T-Cell - genetics

Receptors, Antigen, T-Cell - metabolism

Recombinant Fusion Proteins - genetics

Signal Transduction - genetics

Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics

Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism

ESI Highly Cited Paper (Incites)

Immunotherapy

Lipid Metabolism

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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Title: Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells
Creators: Omkar U Kawalekar - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Roddy S O'Connor - Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Joseph A Fraietta - Drexel University, Biology
Lili Guo - Penn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Shannon E McGettigan - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Avery D Posey, Jr - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Prachi R Patel - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Sonia Guedan - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
John Scholler - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Brian Keith - Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Nathaniel W Snyder - Drexel University, A.J. Drexel Autism Institute
Ian A Blair
Michael C Milone
Carl H June - University of Pennsylvania
Publication Details: Immunity (Cambridge, Mass.), v 44(2), pp 380-390
Publisher: Elsevier
Grant note: T32CA009140 / NCI NIH HHS 5R01CA120409 / NCI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Biology; A.J. Drexel Autism Institute
Web of Science ID: WOS:000370294000019
Scopus ID: 2-s2.0-84958648353
Other Identifier: 991019168498504721

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Highly Cited Paper

Collaboration types: Domestic collaboration
Web of Science research areas: Immunology

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

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