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Thioredoxin-1 Alters Anti-Tumor T Cell Immuno-Metabolic Phenotype

ABSTRACT: ABSTRACT Adoptive transfer of tumor epitope reactive T cells is a promising strategy to control tumor growth. However, chronically stimulated T cells expanded for adoptive cell transfer (ACT) are susceptible to cells death in an oxidative tumor microenvironment. Since oxidation of cell surface thiols (c-SH) also alters functionality of proteins, we hypothesized that increased level of thioredoxin, an anti-oxidant molecule that facilitates reduction of proteins by cysteine thioldisulfide exchange, in T cells will result in sustained anti-tumor function. Using Pmel-Trx1 transgenic mouse derived splenic T cells we observed higher c-SH expression that inversely correlated with ROS, and susceptibility to TCR restimulation or oxidation mediated cell death. These Trx1 overexpressing T cells showed CD62Lhi central memory-like (Tcm) phenotype with reduced glucose uptake (2-NBDGlo) and effector function (IFNγlo). Further, using tumor reactive T cells cultured in presence of recombinant Trx resulted in increased dependence of T cells on mitochondrial metabolism and led to improved tumor control. Thus, strategies to increase antioxidant capacity of anti-tumor T cells modulate its immune-metabolic phenotype leading to improved immunotherapeutic control of established tumors.

ORGANISM(S): Mus musculus

SUBMITTER: Gary Hardiman

PROVIDER: E-MTAB-7571 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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