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.

Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy

“…Despite rapid progress in recent immunotherapies, the response rate of existing anti-PD-1/PD-L1 and/or anti-CTLA-4 therapies in patients overall is far from satisfactory. In a complicated tumour immune environment, the blockade of a single immune checkpoint molecule may induce complementary changes in other immune modulators (11,12,(20)(21)(22)(23). Importantly, therapies targeting new IRs (LAG-3, TIM-3, and TIGIT) are now being applied in clinical trials (registered at ClinicalTrial.gov) or are under active development (12).…”

“…LAG-3, TIM-3, and TIGIT (10)(11)(12)(13). Targeting these IRs may come of age as the second series of immunotherapies is translated to the clinic.…”

“…Therefore, the next question is whether targeting new IRs alone or in combination with existing drugs will achieve clinical e cacy. The answer to this central question is still considerable and requires further discussion, but the combination of IRs with anti-PD-1/PD-L1 blockade may be promising for clinical use based on clinical trials (11,12). Facing the new immuno-oncology era, together we need to decide on the optimal combinations of treatment options for each patient, i.e., second series of IRs (LAG-3, TIM-3, and TIGIT).…”

Identification and Validation of a Predictive Immune-Related Genes Signature for the Prognosis of Cholangiocarcinoma

“…Activation of immune system has been widely proven to be a decisive factor during tumorigenesis and metastasis [28][29][30]. With the development of tumor immunotherapy in recent years, the function of the immune system in the cancer growth and metastasis has been addressed, in which immune cells inhibit or promote malignant cells by up-or down-regulating expression of IRGs [31,32]. Hence, IRGs expression may be an important predictor of prognosis and progression in CCA.…”

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…Then, it revealed that the at least 14 KIR genes have been identified in the human genome and are clustered on Several inhibitory receptors on T and natural killer (NK) cells are classified as immune checkpoint proteins. The discovery of inhibitors against such immune checkpoint proteins, including anti-PD-1 antibodies (nivolumab, pembrolizumab, and cemiplimab), anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody (ipilimumab), anti-lymphocyte activation gene-3 (LAG-3) antibody, anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3) antibody, anti-T cell immunoglobulin ITIM domain (TIGIT) antibody, anti-V-domain Ig suppressor of T cell activation (VISTA) antibody, and anti-killer immunoglobulin-like receptor (KIR2D) antibody (lirilumab), represents a breakthrough in the field of tumor immunotherapy [33,34]. Anti-PD-L1 (ligand for PD-1) antibody (atezolizumab, avelumab, and durvalumab) and anti-CD200 (ligand for CD200 receptor) antibody (samalitumab) target the ligands for inhibitory receptors on these cells [33,35].…”