The role of exhaustion in tumor-induced T-cell dysfunction in cancer

Abstract

T-cells are essential components of the immune system and have been the major focus of immunotherapeutic strategies to boost endogenous antitumor immunity. However, despite homing into tumor sites, infiltrating T-cells seldom control tumor growth, and T-cell-directed immunotherapy has not been successful. Initially, anergy was thought to be responsible for the nonresponsiveness of T-cells to tumors. Nevertheless, cancer has been hypothesized to be a chronic disease, in a similar fashion to chronic viral infections, where T-cells are chronically stimulated. In this scenario, tumor-specific T-cells become dysfunctional, progressively losing effector functions, such as cytolysis or cytokine secretion, a phenomenon known as T-cell exhaustion. In this chapter, we will review the concept of T-cell exhaustion, the mechanisms involved, as well as the markers employed for the identification of exhausted T-cells. To conclude, we discuss the evidence for cancer-induced exhaustion, in particular in lung cancer, in addition to the implications of this phenomenon for tumor immunology.