Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Cell Line, Tumor
  • Glucose Transporter Type 1 / metabolism
  • L-Selectin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Oxidative Stress
  • Phenotype
  • Reactive Oxygen Species / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Tumor Microenvironment
  • gp100 Melanoma Antigen / genetics
  • gp100 Melanoma Antigen / metabolism


  • Antioxidants
  • Glucose Transporter Type 1
  • Pmel protein, mouse
  • Reactive Oxygen Species
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • gp100 Melanoma Antigen
  • L-Selectin
  • Thioredoxins