The role of thymocyte selection-associated HMG box protein (TOX) in CD8 T cell differentiation and dysfunction

Abstract

Abstract CD8 T cells are powerful adaptive immune cells that specifically recognize infected cells and eliminate them. However, in the context of tumors, antigen-specific T cells enter a state of dysfunction allowing tumors to progress. By employing genome-wide transcriptome analysis of dysfunctional tumor-specific T cells (TST) we found that a nuclear factor, thymocyte selection-associated HMG box protein (TOX), was uniquely upregulated during T cell differentiation/dysfunction in progressing tumors, but not during normal CD8 T cell differentiation (e.g. acute infections). TOX is a nuclear DNA-binding factor and member of the high-motility group box superfamily. TOX has been shown to be required for CD4 T cell and NK cell development but its role in peripheral CD8 T cells is not known. We set out to investigate the role of TOX in tumor-specific CD8 T cell differentiation. Using various murine tumor models we found that TOX was uniquely overexpressed in TST within the tumor (TIL) and its overexpression was driven by chronic TCR/antigen stimulation and not by the tumor microenvironment. To understand the role of TOX in CD8 T cell differentiation and dysfunction we are currently conducting TOX genetic knock-out and overexpression studies in vitro and in vivo. The identification and characterization of novel transcriptional regulators such as TOX will provide important insights into the molecular underpinnings defining CD8 T cell dysfunction in tumors.