| First Author | Chakraborty P | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 23 | Pages | 9198-9212 |
| PubMed ID | 30971427 | Mgi Jnum | J:280528 |
| Mgi Id | MGI:6368654 | Doi | 10.1074/jbc.RA118.006753 |
| Citation | Chakraborty P, et al. (2019) Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells. J Biol Chem 294(23):9198-9212 |
| abstractText | 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(hi) (CD62L(hi)) central memory-like phenotype with reduced glucose uptake (2-NBDG(lo)) and decreased effector function (interferon gamma(lo)). 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. |
