Molecular Profiles of Exhausted T Cells and Their Impact on Response to Immune Checkpoint Blockade

T cell exhaustion is induced in the context of chronic virus infection and tumor microenvironment, in which cytotoxic T cells are repeatedly exposed to the target antigen and deprived of their effector functions. Multiple studies have already shown the significant impact of immune checkpoint molecules such as PD1 on functional properties of exhausted T cells. In addition to these signals, exhausted T cells possess distinct transcriptional and epigenetic profiles compared with conventional effector and memory T cells. Importantly, most of these features are not affected by immune checkpoint blockade, suggesting that genetic and epigenetic remodeling of T cells is an underlying molecular mechanism essential for T cell exhaustion. Moreover, it has now been evident that exhausted T cells are a heterogeneous cell population composed of distinct T cell subsets, and these functional differences profoundly affect therapeutic efficacy of cancer immunotherapy. In this review, I will discuss recent studies investigating molecular mechanisms of T cell exhaustion, including novel key molecules essentially associated with T cell exhaustion. These findings are potentially applicable to reinvigorate effector functions of exhausted T cells.