Introductory Chapter: Introduction to New Insights and Recent Progress in Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitor (ICI) is an established therapeutic strategy for various cancers. ICI comprises mainly of monoclonal antibodies that block immune regulatory checkpoint molecules, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death protein-1 (PD-1) and Programmed Death Ligand-1 (PD-L1) [1]. To date, FDA has approved ICIs for various cancer types including anti-CTLA-4 (Ipilimumab, Tremelimumab), anti-PD-1 (Pembrolizumab, Nivolumab, Cemiplimab) and anti-PD-L1 (Atezolizumab, Avelumab, and Durvalumab) [2]. The main mechanism of action of immune checkpoint inhibitors is to target and augment host CD4+ and CD8+ T cell responses. Briefly, CTLA-4 is a T-cell surface receptor that binds costimulatory factors (CD80, CD86) on antigen-presenting cells. This activation transmits inhibitory signal to T cells thus, reducing Interleukin 2 (IL-2) production and T-cell proliferation. Moreover, PD-1 is a cell surface receptor expressed on B cells, T cells and NK cells. Its main function is to promote self-tolerance/prevent autoimmunity via apoptosis of antigen-specific T-cells, suppression of T cell inflammatory activity and downregulation of the immune system. PD-1 has strong binding affinity to its ligands, PD-L1/PD-L2 and this binding delivers a strong inhibitory signal to suppress T cell receptor (TCR) mediated activation of IL-2 production and T cell proliferation for immune regulation [3].