Cancer immunotherapy by targeting immune checkpoints: mechanism of T cell dysfunction in cancer immunity and new therapeutic targets

Tsai and Hsu Journal of Biomedical Science (2017) 24:35 DOI 10.1186/s12929-017-0341-0 REVIEW Open Access Cancer immunotherapy by targeting immune checkpoints: mechanism of T cell dysfunction in cancer immunity and new therapeutic targets Hwei-Fang Tsai1,2 and Ping-Ning Hsu3,4* Abstract Immune checkpoints or coinhibitory receptors, such as cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1, play important roles in regulating T cell responses, and they were proven to be effective targets in treating cancer. In chronic viral infections and cancer, T cells are chronically exposed to persistent antigen stimulation. This is often associated with deterioration of T cell function with constitutive activation of immune checkpoints, a state called ‘exhaustion’, which is commonly associated with inefficient control of tumors and persistent viral infections. Immune checkpoint blockade can reinvigorate dysfunctional/exhausted T cells by restoring immunity to eliminate cancer or virus-infected cells. These immune checkpoint blocking antibodies have moved immunotherapy into a new era, and they represent paradigm-shifting therapeutic strategies for cancer treatment. A clearer understanding of the regulatory roles of these receptors and elucidation of the mechanisms of T cell dysfunction will provide more insights for rational design and development of cancer therapies that target immune checkpoints. This article reviews recent advance(s) in molecular understanding of T cell dysfunction in tumor microenvironments. In addition, we also discuss new immune checkpoint targets in cancer therapy. Keywords: Cancer immunotherapy, Immune checkpoint, T cell exhaustion, New therapeutic targets Background Cancer evades antitumor immune attacks via both inhibiting recognition of cancer specific antigens by T cells and causing dysfunction of CD8 cytotoxic T cells (CTL). Recent breakthroughs and encouraging clinical results with various immune checkpoint inhibitors, such as anti-PD-1 monoclonal antibodies (mAbs) and anti-CTLA-4 mAbs, have demonstrated tremendous potential to control cancer by immune activation [1–9]. Immune checkpoint blockade is able to reinvigorate dysfunctional/exhausted T cells by restoring tumor-specific immunity to eliminate cancer cells. In addition to melanoma, inspiring results were reported in other cancers including lung cancer, * Correspondence: 3 Graduate Institute of Immunology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd, Taipei 100, Taiwan 4 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Full list of author information is available at the end of the article renal cell carcinoma, bladder cancer, and additional approvals are expected, indicating the great promise held by these mAbs. All these results clearly indicate that a new era of immunotherapy has arrived. Long-term control of cancer with durable treatment response now seems achievable. These mAbs have added a new cornerstone to immunotherapy, making it,another key pillar for cancer treatment in the near future. Immune checkpoint blockade has greatly expanded our knowledge of antitumor immunity and has introduced radical changes and new trends in cancer therapy. Moreover, multiple new immune checkpoints that represent potential new targets for cancer therapy are now under active development. This article reviews advance(s) in recent molecular understanding of T cell dysfunction within tumor microenvironments and of developments of new immune checkpoint therapeutic targets for cancer. © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tsai and Hsu Journal of Biomedical Science (2017) 24:35 Immune checkpoints or coinhibitory receptors play critical roles in immune homeostasis To eradicate tumor cells and induce antitumor immunity, T cells are able to recognize tumor antigens presented to T cell receptors (TCRs) by antigen-presenting cells (APCs). After binding to TCR, a second signal (signal two, also called costimulatory signal) is needed for T cell activation. The costimulatory signal comes from the binding of CD28 molecule on T cells with its ligand, B-7 molecules (CD80 and CD86) on APCs. CTLA-4, an immune checkpoint or coinhibitory receptor is induced after T cell activation. CTLA-4 has a higher binding affinity for B-7 ligands than CD28, and CTLA-4 can bind to B7 and displace CD28, leading to attenuation and termination of T cell responses and establishment of tolerance, to minimize the development of autoimmunity. Immune checkpoints or coinhibitory receptors have a central role in regulating autoimmunity, and deficiency of CTLA-4 develops profound lymphoproliferation and systemic autoimmune disease [10, 11]. PD-1 pathway was recognized to play a regulatory role in inhibiting T cell activation and restraining T cell function [12, 13], and PD-1 knockout mice developed proliferative arthritis and a lupus-like autoimmune diseases [14]. Many checkpoint receptors have been genetically associated with autoimmunity and inflammatory diseases [15–18], suggesting that immune checkpoints or coinhibitory receptors play a critical role in immune tolerance and regulating homeostasis. Therefore, immune checkpoints in regulating T cell activation and immune tolerance have been widely studied. More recently, a new frontier in anticancer [6, 19–21] and antiviral therapy [22] has emerged, in which these receptors are being targeted to improve T cell responses [23–25]. CTLA-4 as a coinhibitory receptor for T cell activation The process of T cell activation is tightly regulated by costimulatory signals for full activation, and it is also regulated by coinhibitory signals [26]. The main costimulatory signals for T cell activation are from the B7-1 or B7-2 molecules on antigen presenting cells, which can bind to CD28 on T cells. After binding to its specific antigen ligand, the resulting TCR signals in conjunction with the costimulatory signals from CD28/B7 interaction lead to fully activation of T cells and production of cytokines [27]. CTLA-4 is a major coinhibitory receptor in regulation of T cell response during the priming phase [28]. In contrast to CD28, CTLA-4 delivers an inhibitory signal, and it has a much higher affinity for B7 than CD28 [29, 30]. Thus, CTLA-4 competes for binding to B7, and thereby prevents CD28-mediated T cell costimulation, and also inhibits T cell activation [ (...truncated)