Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

Abstract

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Keywords: B7-H3; BTLA; Immune checkpoint; Immunotherapy; LAG-3; TIGIT; TIM-3; VISTA.

Fig. 1

Structure of LAG-3, TIM-3, TIGIT, VISTA, B7-H3, and BTLA. All of them were type I transmembrane glycoprotein with a similar structure, including N-terminal IgV domain, a transmembrane domain and a cytoplasmic tail. However, they share distinct signaling motif

Fig. 2

Current and emerging immune checkpoint receptors and their respective ligands. Various immune checkpoint molecules expressed on T cells were shown with their ligands. Immune checkpoints such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT bound with their respective ligands on APCs and/or tumor cells, triggering a negative or positive signal to T cells response