Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons

Abstract

The main breakthrough in tumor immunotherapy was the discovery of immune checkpoint (IC) proteins, which act as a potent suppressor of the immune system by a myriad of mechanisms. After that, scientists focused on the immune checkpoint molecules mainly. Thereby, much effort was spent to progress novel strategies for suppressing these inhibitory axes, resulting in the evolution of immune checkpoint inhibitors (ICIs). Then, ICIs have become a promising approach and shaped a paradigm shift in tumor immunotherapies. CTLA-4 plays an influential role in attenuation of the induction of naïve and memory T cells by engagement with its responding ligands like B7-1 (CD80) and B7-2 (CD86). Besides, PD-1 is predominantly implicated in adjusting T cell function in peripheral tissues through its interaction with programmed death-ligand 1 (PD-L1) and PD-L2. Given their suppressive effects on anti-tumor immunity, it has firmly been documented that ICIs based therapies can be practical and rational therapeutic approaches to treat cancer patients. Nonetheless, tumor inherent or acquired resistance to ICI and some treatment-related toxicities restrict their application in the clinic. The current review will deliver a comprehensive overview of the ICI application to treat human tumors alone or in combination with other modalities to support more desired outcomes and lower toxicities in cancer patients. Video Abstract.

Keywords: CTLA-4; Cancer; Immune checkpoint inhibitors; Immunotherapy; PD-1/PD-L1.

Fig. 1

The inhibitory effects of the CTLA-4/B7 on T cell anti-tumor activities. CTLA-4 is expressed on activated T cells, is about 30% homologous with CD28 and binds to the same ligands as CD28, known as B7-1 and B7-2 expressed on APCs or tumor cells. This interaction results in activation of SHP2 and so down-regulation of PI3K/AKT axis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), SH2 containing protein tyrosine phosphatase-2 (SHP2), Phosphoinositide 3-kinases (PI3Ks), Phosphatidylinositol-4,5-bisphosphate (PIP2), Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), Lymphocyte-specific protein tyrosine kinase (LCK), T cell receptor (TCR), Nuclear factor-κB (NF-κB), Mammalian target of rapamycin (mTOR), B-cell lymphoma-extra large (Bcl-xL), Major histocompatibility complex class II (MHCII), Interleukin-2 (IL-2)

Fig. 2

The inhibitory effects of the PD-1/PD-L interactions on T cell anti-tumor activities. PD-L1 expressed on APCs or tumor cells following interaction with PD-1 dysregulated on the surface of activated T cell limits self-reactive T cell proliferation and cytokine production as a result of activation of SHP2, which down-regulates PI3K/AKT axis. Programmed cell death protein 1(PD-1), Programmed death-ligand 1 and 2 (PD-L1, PD-L2), Antigen-presenting cells (APCs), SH2 containing protein tyrosine phosphatase-2 (SHP2), Phosphoinositide 3-kinases (PI3Ks), Phosphatidylinositol-4,5-bisphosphate (PIP2), Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), Lymphocyte-specific protein tyrosine kinase (LCK), T cell receptor (TCR), Nuclear factor-κB (NF-κB), Mammalian target of rapamycin (mTOR), B-cell lymphoma-extra large (Bcl-xL), Major histocompatibility complex class II (MHCII), Interleukin-2 (IL-2)

Fig. 3

Clinical trials based on tumor immunotherapy using immune checkpoint inhibitors (ICIs) registered in ClinicalTrials.gov (November 2021). The schematic illustrates clinical trials using ICIs depending on the study phase (A), study status (B), conditions (C), and agents (D) in cancer patients