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Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adoptive cell therapy (ACT) employing ex vivo-generated tumor antigen-specific CD8+ T cells shows tumor efficacy when the transferred cells possess both effector and memory functions. New strategies based on understanding of mechanisms that balance CD8+ T cell differentiation toward effector and memory responses are highly desirable. Emerging information confirms a central role for antigen-induced metabolic reprogramming in CD8+ T cell differentiation and clonal expansion. The mitochondrial protein uncoupling protein 2 (UCP2) is induced by antigen stimulation of CD8+ T cells; however, its role in metabolic reprogramming underlying differentiation and clonal expansion has not been reported. Employing genetic (siRNA) and pharmacologic (Genipin) approaches, we note that antigen-induced UCP2 expression reduces glycolysis, fatty acid synthesis and production of reactive oxygen species to balance differentiation with survival of effector CD8+ T cells. Inhibition of UCP2 promotes CD8+ T cell terminal differentiation into short-lived effector cells (CD62LloKLRG1HiIFNγHi) that undergo clonal contraction. These findings are the first to reveal a role for antigen-induced UCP2 expression in balancing CD8+ T cell differentiation and survival. Targeting UCP2 to regulate metabolic reprogramming of CD8+ T cells is an attractive new approach to augment efficacy of tumor therapy by ACT.

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Abbreviations

ACT:

Adoptive cell therapy

CM-H2DCFDA:

5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester

cROS:

Cytoplasmic reactive oxygen species

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

ECAR:

Extracellular acidification rate

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

FAS:

Fatty acid synthesis

mROS:

Mitochondrial reactive oxygen species

NAD+/NADH:

Nicotinamide adenine dinucleotide/dehydrogenase

OCR:

Oxygen consumption rate

OXPHOS:

Oxidative phosphorylation

PCR:

Polymerase chain reaction

PD-1/PD-L1:

Programmed cell death protein 1/ligand

PDH:

Pyruvate dehydrogenase

ROS:

Reactive oxygen species

SRC:

Spare respiratory capacity

TCA:

Tricarboxylic acid cycle

TCR:

T cell receptor

UCP2:

Uncoupling protein 2

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Acknowledgments

We thank all current and past members of the Shrikant laboratory for critical review, comments and discussions. This work was supported by the NIH National Cancer Institute (NCI) (P50CA158318-3, Protul A. Shrikant).

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Author notes

  1. Rupesh K. Srivastava

    Present address: Department of Zoology, School of Biological Sciences, Dr. Hari Singh Gour University, Sagar, MP, 470003, India

  2. Ferdynand Kos

    Present address: Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

Authors and Affiliations

  1. Departments of Immunology, Molecular Pharmacology/Experimental Therapeutics and Research, Mayo Clinic Arizona, JRB 3-356, E. Shea Blvd, Scottsdale, AZ, 85259, USA

    Leena Chaudhuri, Rupesh K. Srivastava, Ferdynand Kos & Protul A. Shrikant

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  1. Leena Chaudhuri
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  2. Rupesh K. Srivastava
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Correspondence to Protul A. Shrikant.

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Additional information

This paper is a Focussed Research Review based on a presentation given at the Fourth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2015), held in Ljubljana, Slovenia, 27th–30th April 2015. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.

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Chaudhuri, L., Srivastava, R.K., Kos, F. et al. Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells. Cancer Immunol Immunother 65, 869–874 (2016). https://doi.org/10.1007/s00262-016-1851-4

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  • DOI: https://doi.org/10.1007/s00262-016-1851-4

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