title: Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.
abstract: 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.
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Omkar U
authors.initials: OU
authors.lastname: Kawalekar
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Roddy S
authors.initials: RS
authors.lastname: O'Connor
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fraietta
authors.affiliation: 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.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McGettigan
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Avery D
authors.initials: AD
authors.lastname: Posey
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Prachi R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Guedan
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Scholler
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: 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; A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Snyder
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: 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.
authors.forename: Ian
authors.initials: I
authors.lastname: Blair
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Milone
authors.affiliation: Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: cjune@exchange.upenn.edu.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology*; D019069:Cell Respiration; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D050356:Lipid Metabolism; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D019496:Cancer Vaccines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9