Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy

Madhusudhanan Sukumar, Jie Liu, Gautam U. Mehta, Shashank J. Patel, Rahul Roychoudhuri, Joseph G. Crompton, Christopher A. Klebanoff, Yun Ji, Peng Li, Zhiya Yu, Greg D. Whitehill, David Clever, Robert L. Eil, Douglas C. Palmer, Suman Mitra, Mahadev Rao, Keyvan Keyvanfar, David S. Schrump, Ena Wang, Francesco M. MarincolaLuca Gattinoni, Warren J. Leonard, Pawel Muranski, Toren Finkel, Nicholas P. Restifo

Research output: Contribution to journalArticle

110 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)63-76
Number of pages14
JournalCell Metabolism
Volume23
Issue number1
DOIs
Publication statusPublished - 12-01-2016

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Sukumar, M., Liu, J., Mehta, G. U., Patel, S. J., Roychoudhuri, R., Crompton, J. G., Klebanoff, C. A., Ji, Y., Li, P., Yu, Z., Whitehill, G. D., Clever, D., Eil, R. L., Palmer, D. C., Mitra, S., Rao, M., Keyvanfar, K., Schrump, D. S., Wang, E., ... Restifo, N. P. (2016). Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. Cell Metabolism, 23(1), 63-76. https://doi.org/10.1016/j.cmet.2015.11.002