In the context of chronic antigen exposure in chronic viral infections and cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit defective proliferative capacities and cytokine production, but are not totally inert and may exert lytic functions. Importantly, exhausted T cells upregulate multiple inhibitory receptors/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (TME). Immune checkpoint blockades with anti-CTL antigen 4 (CTLA-4) and/or anti-programmed death 1 (PD-1) mAbs successfully reinvigorate tumor-infiltrating T lymphocytes and provide persistent clinical benefits to a large number of patients with advanced cancer. This great and long-awaited success for the immunotherapy of cancer has infused considerable enthusiasm in the field of oncology and fostered the development of combinatorial strategies to target the multiple mechanisms of tumor-induced T-cell dysfunction. Here, we review the critical immunoregulatory mechanisms driving T-cell exhaustion in the TME. We also discuss the development of promising combinatorial immunotherapies to counteract the mechanisms of tumor-induced T-cell dysfunction to improve the clinical efficacy of current immune checkpoint blockades. As our understanding of the mechanisms supporting tumor-induced T-cell dysfunction improves based upon preclinical and clinical studies, we expect that novel combinatorial immunotherapies will emerge to improve the clinical outcome of patients with advanced cancers. Clin Cancer Res; 22(8); 1856–64. ©2016 AACR.

See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”