Targets of Immune Escape Mechanisms in Cancer: Basis for Development and Evolution of Cancer Immune Checkpoint Inhibitors

Abstract

Immune checkpoint blockade (ICB) has emerged as a novel therapeutic tool for cancer therapy in the last decade. Unfortunately, a small number of patients benefit from approved immune checkpoint inhibitors (ICIs). Therefore, multiple studies are being conducted to find new ICIs and combination strategies to improve the current ICIs. In this review, we discuss some approved immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and also highlight newer emerging ICIs. For instance, HLA-E, overexpressed by tumor cells, represents an immune-suppressive feature by binding CD94/NKG2A, on NK and T cells. NKG2A blockade recruits CD8+ T cells and activates NK cells to decrease the tumor burden. NKG2D acts as an NK cell activating receptor that can also be a potential ICI. The adenosine A2A and A2B receptors, CD47-SIRPα, TIM-3, LAG-3, TIGIT, and VISTA are targets that also contribute to cancer immunoresistance and have been considered for clinical trials. Their antitumor immunosuppressive functions can be used to develop blocking antibodies. PARPs, mARTs, and B7-H3 are also other potential targets for immunosuppression. Additionally, miRNA, mRNA, and CRISPR-Cas9-mediated immunotherapeutic approaches are being investigated with great interest. Pre-clinical and clinical studies project these targets as potential immunotherapeutic candidates in different cancer types for their robust antitumor modulation.

Keywords: CRISPR-Cas9 cancer immunotherapy; cancer therapeutic strategy; cancer treatment; immune checkpoint inhibitors; immune response; immune-oncology; mRNA cancer immunotherapy; tumor immune escape; tumor immune microenvironment.

Figure 1

Key immune checkpoint targets for cancer immunotherapy mentioned in this review. Immune checkpoint inhibitors (ICIs) and their respective ligands are reported in the context of the tumor immune microenvironment (TME). Various immune checkpoint target-mediated interactions between immune cells such as dendritic cells (DC) (serving as APCs), T cells, NK cells, and tumor cells are shown here. Mechanisms of action of all the checkpoint proteins mentioned here have been elaborated in their respective sections in this review. ICIs targeting these immune checkpoints are currently used in clinic or under pre-clinical or clinical investigation. The “?” indicates interactions which are unknown/uncertain. This figure has been created with BioRender.com, access date 22 January 2023.