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J Biol Chem. 2019 Jun 7;294(23):9198-9212. doi: 10.1074/jbc.RA118.006753. Epub 2019 Apr 10.

Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells.

Author information

1
From the Departments of Surgery.
2
Microbiology and Immunology.
3
the Department of Surgery, Loyola University, Maywood, Illinois 60153, and.
4
Biochemistry and Molecular Biology.
5
Nephrology.
6
the Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut 06030.
7
Pharmaceutical and Biomedical Sciences, and.
8
Public Health, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425.
9
From the Departments of Surgery, mehrotr@musc.edu.

Abstract

Adoptive transfer of tumor epitope-reactive T cells has emerged as a promising strategy to control tumor growth. However, chronically-stimulated T cells expanded for adoptive cell transfer are susceptible to cell death in an oxidative tumor microenvironment. Because oxidation of cell-surface thiols also alters protein functionality, we hypothesized that increasing the levels of thioredoxin (Trx), an antioxidant molecule facilitating reduction of proteins through cysteine thiol-disulfide exchange, in T cells will promote their sustained antitumor function. Using pre-melanosome protein (Pmel)-Trx1 transgenic mouse-derived splenic T cells, flow cytometry, and gene expression analysis, we observed here that higher Trx expression inversely correlated with reactive oxygen species and susceptibility to T-cell receptor restimulation or oxidation-mediated cell death. These Trx1-overexpressing T cells exhibited a cluster of differentiation 62Lhi (CD62Lhi) central memory-like phenotype with reduced glucose uptake (2-NBDGlo) and decreased effector function (interferon γlo). Furthermore, culturing tumor-reactive T cells in the presence of recombinant Trx increased the dependence of T cells on mitochondrial metabolism and improved tumor control. We conclude that strategies for increasing the antioxidant capacity of antitumor T cells modulate their immunometabolic phenotype leading to improved immunotherapeutic control of established tumors.

KEYWORDS:

T-cell; adoptive cell therapy; antioxidant; cell metabolism; cell-surface thiol; immunotherapy; melanoma; redox protein; thioredoxin

PMID:
30971427
PMCID:
PMC6556575
[Available on 2020-06-07]
DOI:
10.1074/jbc.RA118.006753

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