Table 2 Summary of molecules involved in the immune regulation, their ligands, and functions
No | Checkpoint receptor | Expressed cells examples | Ligand | Affected cells examples | Functions | Ref |
|---|---|---|---|---|---|---|
1 | CTLA-4 (CD152) | 1. Regulatory T cells 2. Activated T cells 3. Monocyte-derived dendritic cells 4. B cells 5. NK cells 6. Tumor cells | 1. CD80 2. CD86 | 1. Dendritic cells 2. Macrophage 3. Monocytes | 1. Mediate opposing functions in T cell activation 2. Inhibits T-cell activation and proliferation 3. ↓ Cytotoxic T lymphocytes 4. Hemoestasis of immune responses 5. Play a crucial regulator role in self-tolerance | |
2 | PD-1 (CD279) | 1. Activated T cells 2. NK cells 3. B cells 4. Macrophages 5. Several subsets of DCs 6. Innate-like lymphocytes (ILCs) | 1. PD-L1 2. PD-L2 3. Galectin 9 | 1. Cancer cells 2. PD-L1 expressed by different cells 3. PD-L2 expression is restricted to DC and macrophages | 1. Inhibit the effector function of CD8+ T 2. ↓ T cell proliferation 3. ↓ T cell cytokine production 4. Affect on epigenetic programs in tumor-infiltrated CD8+ T 5. ↑ T cell exhaustion | |
3 | TIM-3 (CD366) | 1. IFN-γ-producing T cells 2. Terminally exhausted T cells 3. FoxP3+ Treg cells 4. Macrophages 5. DCs 6. Tumor cells 7. NK/NKT cells | 1. Galectin 9 2. Ceacam1 3. HMGB1 4. phosphatidylserine | 1. Th1 cells 2. CD8+ T cell | 1. ↑ Aggregation and death of Th1 cell in vitro 2. Inhibiting Th1 responses and the production of TNF-α and IFN-γ 3. Role in dominating the tumor-infiltrating CD8+ T cell pool in some cancer types | |
4 | LAG-3 (CD223) | 1. Regulatory T cells 2. Activated CD4+ T cell 3. Activated CD8+ T cell 4. Exhausted CD8 + T cells 5. NK cells 6. MAIT 7. γδT cells 8. iNKT cells 9. Tr1 | 1. MHC class II 2. FGL-1 3. α-synuclein fibrils 4. Gal-3 5. LSECtin | 1. Antigen-presenting cells 2. Somatic cells | 1. Improves the function of Treg cell 2. ↓ T cells proliferation 3. ↓ T cell cytokine and granzyme production 4. Suppress tumor-specific T-cell functions | |
5 | TIGIT and CD96 | 1. Intratumoral T cells 2. Regulatory T cells 3. Follicular T helper cells 4. NK cells 5. Tumor cells | 1. CD155 (PVR) 2. CD112 (PVRL2, nectin-2) 3. Fap2 4. Nectin-4 | 1. DCs 2. Tumor cells | 1. Act as a negative regulator of T cell functions 2. ↓ TCR expression and signaling 3. Upregulates CCR8 expression in Treg, which may promote migration to tumor tissue 4. Suppress Th1 and Th17 cells function 5. ↑ immunosuppressive cytokine production like IL-10 | |
6 | BTLA (CD272) | 1. Activated T cells 2. Naïve T cells 3. Naïve B cells 4. NK cells 5. Macrophages 6. DCs | HVEM | 1. T cells 2. B cells 3. NK cells 4. DCs 5. Myeloid cells 6. Tumor cells | 1. Blocks B and T cell activation 2. ↓ B and T cell proliferation 3. ↓ B cell, T cell, and DC cytokine production 4. ↑ Treg and Th2 differentiation | |
7 | A2AR | 1. Regulatory T cells 2. Cytotoxic T cells 3. Macrophages 6. Tumor cells | Adenosine | Adenosine is produced by CD39 and CD73 expressing cells and released to the extracellular environment | 1. Modulate alpha-synuclein aggregation and toxicity 2. ↑ IL-10 production by immune cells 3. ↓ NF-κB signaling pathway 4. ↓ Immune cells protein synthesis 5. ↓ Immune cell proliferation and survival | |
8 | CD24 | 1. Regulatory T cells 2. B10 regulatory B cells 3. Hematopoietic cells 4. Neutrophils 5. Eosinophils 6. Macrophages 7. Dendritic cells 8. Non-hematopoietic cells 9. Tumor cells | 1. Siglec-10 2. P-selectin | 1. B cells 2. Monocytes 3. Dendritic cells 4. Activated CD4+ T cells | 1. T-cell homeostatic proliferation in lymphopenic hosts 2. Promoting cell migration 3. Role in the development of the human central nervous system 4. ↑ Tumor cell proliferation | |
9 | SIRPα (CD172a) | 1. Monocytes 2. Granulocytes 3. DCs 4. Hematopoietic stem cells | CD47 | 1. Thymocytes 2. T and B cells 3. Monocytes 4. Platelets 5. Erythrocytes 6. Neural cells 7. Fibroblasts 8. Tumor cell | 1. Act as a negative regulator of the PI3K and MAPK 2. Leads to reduced responsiveness to tyrosine kinase ligands 3. ↑ Cancer cell proliferation 4. ↓ T cell-mediated antitumor responses 5. Prevents the phagocytic synapse formation on myeloid cells 6. Prevent virus-infected and bacteria-infected cells immune-mediated elimination | |
10 | LILRB1 | 1. B cells 2. T cells 3. Monocytes and macrophages 4. Dendritic cells 5. NK cells 6. Basophils 7. Eosinophils 8. γδ T cells | 1. HLA class I molecules including HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G 2. S100A8 3. S100A9 4. RIFINs | 1. Somatic cells 2. APCs | 1. Inhibits super-antigen–dependent cell cytotoxicity 2. Impairs B-cell antibody production and proliferation 3. Role in immune tolerance 4. Alters DCs differentiation 5. Chang DCs capacity in cytokines production | |
11 | VISTA | 1. Myeloid lineage-related cells, including MDSCs 2. Haematopoietic cells 3. Tumor cells 4. Activated CD4+ T cells 5. Activated CD8+ T cells | 1. PSGL-1 2. VSIG3 | 1. Brain cells 2. Testis cells 3. Skeletal muscle cells 4. Tumor cells | 1. Suppresses proliferation of T cells 2. Bluntes T cell cytokines production and activation markers 3. Induces Foxp3 expression in T cells 4. ↓ Tumour-infiltrating CD8 + T cells in vivo 5. ↓ IFNγ, IL-2, IL-6 and IL-12 production from T cells 6. ↓ Toll-like receptor (TLR) signaling 7. ↓ Cell migration 8. ↑ IL-10 and other anti-inflammatory mediators production | |
12 | Killer cell immunoglobulin-like receptors (KIR) | 1. NK cells 2. T cells | 1. MHC class I | Nearly every normal nucleated cell | 1. Development of NK cells 2. Tolerance of NK cells 3. Activation of NK cells 4. ↓ T cell effector function 5. ↓ T cell activation-induced cell death (AICD) | |
13 | C-lectin-type-inhibitory receptors (CLIRs), including DCIR | 1. Myeloid cells, including DCs and macrophages 2. Osteoclasts | Asialo-biantennary N-glycan (NA2) | 1. Bone cells 2. Myeloid cells | 1. ↓ TLR8-dependent IL-12 and TNFα production from DCs 2. ↓ Pro-inflammatory cytokines IL-1β and IL-6 frpm macrophages 3. ↓ IL12p70 production and DC-dependent TH1 skewing 4. Inhibited osteoclastogenesis | |
14 | Inhibitory Siglec receptors | 1. Immune effector cells 2. Trophoblasts 3. Myelin-forming cells 4. Stromal cells | Sialoglycans such as α2,3/6-linked sialic acid | 1. Stromal cells 2. Immune cells 3. Cancer-associated fibroblasts | 1. ↑ Production of immunosuppressive cytokines 2. Dampen activation of antigen-presenting cells 3. Inhibit NK activation 4. ↑ Differentiation of MQs immunosuppressive M2 phenotype 5. ↑ Antigen-specific Tregs population 6. ↓ Proliferation of effector T cells 7. Shaping MSC/CAF immunosuppression in the TME |