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 her... More
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 62L (CD62L) central memory-like phenotype with reduced glucose uptake (2-NBDG) and decreased effector function (interferon γ). 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.
