title: Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy.
abstract: Long-term survival and antitumor immunity of adoptively transferred CD8(+) T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8(+) T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8(+), CD4(+) T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: sukumarm2@mail.nih.gov.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Sukumar
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Gautam U
authors.initials: GU
authors.lastname: Mehta
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; NIH-Georgetown University Graduate Partnership Program, Georgetown University Medical School, Washington, DC 20057, USA.
authors.forename: Shashank J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Roychoudhuri
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Crompton
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Clinical Investigator Development Program, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.affiliation: Experimental Transplantation and Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Hematology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Greg D
authors.initials: GD
authors.lastname: Whitehill
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: David
authors.initials: D
authors.lastname: Clever
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eil
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Thoracic and GI Oncology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.affiliation: Hematology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Thoracic and GI Oncology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Experimental Transplantation and Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: Hematology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.affiliation: Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: restifo@nih.gov.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000502:physiology* / Q000637:transplantation; D008546:Melanoma, Experimental / Q000628:therapy*; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D033581:Stem Cell Transplantation; D016176:T-Lymphocyte Subsets / Q000502:physiology* / Q000637:transplantation; D059467:Transcriptome
chemical_list: D016207:Cytokines