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. Marincola & 5 others Luca Gattinoni, Warren J. Leonard, Pawel Muranski, Toren Finkel, Nicholas P. Restifo

Research output: Contribution to journalArticle

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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

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Mitochondrial Membrane Potential
T-Lymphocytes
Therapeutics
Metabolomics
T-Lymphocyte Subsets
Gene Expression Profiling
Hematopoietic Stem Cells
Immunity
Neoplasms
Coloring Agents
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Sukumar, M., Liu, J., Mehta, G. U., Patel, S. J., Roychoudhuri, R., Crompton, J. G., ... 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
Sukumar, Madhusudhanan ; Liu, Jie ; Mehta, Gautam U. ; Patel, Shashank J. ; Roychoudhuri, Rahul ; Crompton, Joseph G. ; Klebanoff, Christopher A. ; Ji, Yun ; Li, Peng ; Yu, Zhiya ; Whitehill, Greg D. ; Clever, David ; Eil, Robert L. ; Palmer, Douglas C. ; Mitra, Suman ; Rao, Mahadev ; Keyvanfar, Keyvan ; Schrump, David S. ; Wang, Ena ; Marincola, Francesco M. ; Gattinoni, Luca ; Leonard, Warren J. ; Muranski, Pawel ; Finkel, Toren ; Restifo, Nicholas P. / Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. In: Cell Metabolism. 2016 ; Vol. 23, No. 1. pp. 63-76.
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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.",
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Sukumar, M, Liu, J, Mehta, GU, Patel, SJ, Roychoudhuri, R, Crompton, JG, Klebanoff, CA, Ji, Y, Li, P, Yu, Z, Whitehill, GD, Clever, D, Eil, RL, Palmer, DC, Mitra, S, Rao, M, Keyvanfar, K, Schrump, DS, Wang, E, Marincola, FM, Gattinoni, L, Leonard, WJ, Muranski, P, Finkel, T & Restifo, NP 2016, 'Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy', Cell Metabolism, vol. 23, no. 1, pp. 63-76. https://doi.org/10.1016/j.cmet.2015.11.002

Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. / Sukumar, Madhusudhanan; Liu, Jie; Mehta, Gautam U.; Patel, Shashank J.; Roychoudhuri, Rahul; Crompton, Joseph G.; Klebanoff, Christopher A.; Ji, Yun; Li, Peng; Yu, Zhiya; Whitehill, Greg D.; Clever, David; Eil, Robert L.; Palmer, Douglas C.; Mitra, Suman; Rao, Mahadev; Keyvanfar, Keyvan; Schrump, David S.; Wang, Ena; Marincola, Francesco M.; Gattinoni, Luca; Leonard, Warren J.; Muranski, Pawel; Finkel, Toren; Restifo, Nicholas P.

In: Cell Metabolism, Vol. 23, No. 1, 12.01.2016, p. 63-76.

Research output: Contribution to journalArticle

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T1 - Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy

AU - Sukumar, Madhusudhanan

AU - Liu, Jie

AU - Mehta, Gautam U.

AU - Patel, Shashank J.

AU - Roychoudhuri, Rahul

AU - Crompton, Joseph G.

AU - Klebanoff, Christopher A.

AU - Ji, Yun

AU - Li, Peng

AU - Yu, Zhiya

AU - Whitehill, Greg D.

AU - Clever, David

AU - Eil, Robert L.

AU - Palmer, Douglas C.

AU - Mitra, Suman

AU - Rao, Mahadev

AU - Keyvanfar, Keyvan

AU - Schrump, David S.

AU - Wang, Ena

AU - Marincola, Francesco M.

AU - Gattinoni, Luca

AU - Leonard, Warren J.

AU - Muranski, Pawel

AU - Finkel, Toren

AU - Restifo, Nicholas P.

PY - 2016/1/12

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N2 - 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.

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Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG et al. Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. Cell Metabolism. 2016 Jan 12;23(1):63-76. https://doi.org/10.1016/j.cmet.2015.11.002