Increased expression of anti-oxidant molecule Thioredoxin-1 on T cells improves immunotherapeutic control of tumors (VAC7P.1039)

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 thiol-disulfide exchange, in T cells will result in sustained anti-tumor function. We thus crossed Trx1 transgenic mice with gp100 reactive TCR (Pmel) to generate Pmel/Trx mice. The Trx overexpressing transgenic T cells expressed higher thiols that inversely correlated with ROS, and susceptibility to TCR restimulation or H2O2 mediated cell death. These Trx1 expressing T cells showed CD62Lhi central memory-like (TCM) phenotype with reduced effector function (IFNglo2-NBDGlo), and were less effective in controlling tumor upon adoptive transfer. However, adoptive transfer of Pmel cells mixed with Pmel/Trx1 cells in 1:1 ratio markedly improved tumor control as compared to the mice that were transferred Pmel or Pmel/Trx T cells alone. It is likely that Pmel immediate effectors and Pmel/Trx cells with T-stem cell memory phenotype (i.e. CD62LhiCD44loCD122+Sca1hi), contributed to the improved tumor control. Thus, strategies to increase anti-oxidant capacity of anti-tumor T cells could have immunotherapeutic implications.