Immune Checkpoint Proteins

It’s mainly expressed in activated CD4+ and CD8+ T cell, which accounts for about 33% and 31% in unstimulated whole blood respectively. Besides, it’s also expressed in B cell, NKT cell, dendritic cell, monocyte. However, there are many different viewpoints on whether human NK cells express PD-1. Till now, there are three FDA approved inhibitors against PD-1 and PD-L1 respectively: Nivolumab, Pembrolizumab and Cemiplimab(PD-1); Atezolizumab, Avelumab, Durvalumab(PD-L1).

CTLA-4 switches to terminate immune reaction via binding with receptors on antigen cell surface. CTLA-4 inhibitor can increase the cell proliferation to attack tumor cells via inhibiting CTLA-4 molecule. Currently, Ipilimumab is the only FDA approved CTLA-4 inhibitor.

VISTA is the important regulator for immune homeostasis and antitumor immunity. In immunocytes, VISTA is mainly expressed by myeloids(e.g. neutrophils, monocytes, macrophages, and dendritic cells etc). Naïve T cell and CD4+ T cell weakly express VISTA. The expression level of VISTA in CD8+ T cell, Foxp3+ Treg and CD56dim NK cell is even lower. However, CD56bright NK cell and B cell mostly express negativity of VISTA.

Current researches show VISTA blocker improves the active state of tumor-associated dendritic cells and produces more inflammatory cells to up-regulate costimulation of these cell and antigen-presenting molecules. Thus, VISTA is expected to improve antigen-presenting function of myeloid cells in tumor draining lymph nodes and increase the potential of activation of tumor-reactive T cells and function of effector.

TIM-3 consists of a extracellular domain, a single transmembrane domain and a C-terminal cytoplasmic tail. TIM-3 exists in different types of immunocytes as a negatively regulating immune checkpoint, including T cells, NK cells, monocytes, macrophages and DCs.

TIM-3 can regulate antitumor immunity by binding with different ligands. E.g. Binding between Galectin-9 and sugar chain of TIM-3 regulates immunity of TH1 cell via inducing apoptosis. Interaction between HMGB1 and TIM-3 damages toll-like receptors and cytoplasmic receptor induced innate immune response for nucleic acid, preventing effects of DNA vaccine and cytotoxic chemotherapy.

Mainly expressed in activated T cells, NK cells, B cells, plasma cells and dendritic cells.

TIGIT is expressed in CD4+ T cells, CD8+ T cells, NK cells and Treg cells, inhibiting innate and adaptive immunity via various mechanisms.

TIGIT can inhibit CD155 mediated activation of CD226, involved in activating TCR signaling pathway and recognizing NK cell neoplasm. In unstimulated whole blood sample of healthy individuals, 13% CD4+ T cells and 24% CD8+ T cells express TIGIT. TIGIT can up-regulate in damaged CD8+ T cells. Double chemical-block of TIGIT and PD-1 can partially restore the ability of CD8+ T cell. Besides, there are significant individual differences for the expression of TIGIT in NK cells(about 20%-90%, avg 62.57%). Expression level in CD56dim NK cells is higher than CD56bright NK cell.

SIRPα is a typical inhibitory immune receptor of SIRP family. Binding with its ligand CD47 prevents macrophages from phagocytizing healthy cells. Cancer cells can also escape the immunosurveillance. SIRPα isn’t widely expressed in human body. Its expression was found mainly in surface of myeloid cells(monocytes, macrophages, granulocytes, and myeloid DC cells etc) and neuronal cells of nervous system.

It has extracellular immunoglobulin domains, immunoreceptor tyrosine-based inhibitory motif(ITIM) and switch motif(ITSM). Signal transduction of BTLA includes phosphorylation of ITIMs and binding with SH2 domain-containing phosphatases(SHP-1/SHP-2) to inhibit proliferation of T cell and production of cytokines.

siglec7 is expressed in NK cells, monocytes, macrophages, and neutrophils. Similar with classical NK cell inhibitory receptor NKG2A/CD94 and KIRs, inhibitory siglec also contains single or multiple ITIM and ITIM like motif in intracellular C-terminal segment. The linked ITIM is phosphorylated by Sr family kinase, recruits and activates Src homology-2 (SH2) domain proteins, mainly including tyrosine phosphatase SHP1/SHP2 or cytokine signal transduction inhibitor(SOCS3).

The protein extracellular region has Ig-like domain. Intracellular region has ITIM motif. The family members include LILRB1, LILRB2, LILRB3, LILRB4, LILRB5.

LILRB2(also called ILT3, CD85k) is mainly expressed in myeloid cells, including monocytes, dendritic cells, macrophages, and neutrophils.

LILRB4(also called ILT3, CD85k) plays a very important role in function of the immune system via expressing in various immunocytes(e.g. T cell and plasma cell) under physiological conditions. LILRB4 is mainly expressed in APC as immune tolerance receptor. Besides, APCs expressed by LILRB4 plays a key role in controlling inflammation. LILRB4 is also the important marker for monocytic leukemia, supports infiltration of tumor cell and inhibits activity of T cell in acute myeloid leukemia cells(AML) via the signal axis ApoE/LILRB4/SHP-2/uPAR/Arginase-1. Blocking the signal transduction of LILRB4 can restrict the development of AML. Thus, LILRB4 is the important target for treating monocytic acute myeloid leukemia.