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; Luca Gattinoni; Warren J. Leonard; Pawel Muranski; Toren Finkel; Nicholas P. Restifo

doi:10.1016/j.cmet.2015.11.002

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 journal › Article › peer-review

261 Scopus citations

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 language	English (US)
Pages (from-to)	63-76
Number of pages	14
Journal	Cell Metabolism
Volume	23
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2015.11.002
State	Published - Jan 12 2016
Externally published	Yes

ASJC Scopus subject areas

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

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

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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.",

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

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doi = "10.1016/j.cmet.2015.11.002",

language = "English (US)",

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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

Y1 - 2016/1/12

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.

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

Abstract

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