Reversing T-cell Dysfunction and Exhaustion in Cancer #MMPMID27084739
Zarour HM
Clin Cancer Res 2016[Apr]; 22 (8): 1856-64 PMID27084739show ga
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 (IRs)/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells (APCs) in the tumor microenvironment (TME). Immune checkpoint blockades with anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and/or anti- programmed death 1 (PD-1) monoclonal antibodies (mAbs) successfully reinvigorate tumor-infiltrating T lymphocytes (TILs) 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 propose to review the critical immunoregulatory mechanisms driving T cell exhaustion in the TME. We will 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.
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Clin+Cancer+Res 2016 ; 22 (8): 1856-64
