Table 1.
Immune regulatory receptor drug targets
| Stimulatory Receptors | Effector Signaling Pathways Upregulated | Inhibitory Receptors | Effector Signaling Pathways Downregulated |
|---|---|---|---|
| CD28 (14–17) | PI3K-AKT, ERK, T-bet, Eomes, GATA3, AP-1, NFAT, NF-κB (18, 19) | CTLA4 (CD152) (14, 16, 17, 20) | PI3K-AKT, AP-1, NF-κB, NFAT, MAPK (21, 22) |
| ICOS (14–17) | JNK, PI3K-AKT-mTOR-NFAT (23, 24) | PD-1 (CD279) (14, 16, 17, 20) | MAPK, PI3K-AKT, AP-1, NFAT, NF-κB (21, 25) |
| HVEM (17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT, AP-1 (26, 27) | BTLA (17, 28) | Binds with CD160, reduced CD3 signaling, NF-κB, AKT, STAT3 (29–31) |
| CD27 (15–17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27, 32) | TIM-3 (14, 17, 20) | Binds to Galectin-9/Bat3, PI3K-AKT, NF-κB (33, 34) |
| 4-1BB (CD137) (14–17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27, 35) | TIGIT (14, 17, 20) | ZAP70/Syk, ERK (36), PI3K (37) |
| OX-40 (CD134) (14–17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27, 38) | CD160 (17) | Binds with BTLA, reduced CD3 signaling (30, 31), p56, PI3K (26) |
| DR3 (17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27, 39) | LAG-3 (14, 17, 18) | STAT5, AKT (40) |
| GITR (14, 17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27) | LAIR1 (17) | JAK/STAT, MAPK (26) |
| CD30 (16, 17) | TRAF recruitment, NF-κB, MAPK, PI3K-AKT (27) | B7-1 (14, 17) | NF-κB (41) |
| SLAM (15, 17) | PI3K/Akt/mTOR, NF-κB, MAPK (42) | NRP1 (20) | MAPK, PI3K (43) |
| CD2 (17) | mTOR, AMPK, MAPK (44) | CCR4 (45) | MAPK, PLC, PI3K (46) |
| TIM-2 (17) | Largely still unknown | VISTA (47) | Largely still unknown |
| CD226 (14, 17) | PI3K-AKT, ERK, FOXO1 (48) | ||
| LFA-1 (CD11A/CD18) (15) | PI3K (49) |
Immune stimulatory and inhibitory receptors are common drug targets for immunotherapy. Among these targets is PD-1, the target for pembrolizumab. Other drug-targeting therapies have been used in conjunction with pembrolizumab to rapidly reduce and eliminate tumor burden. AMPK, AMP-activated kinase; AP-1, activator protein 1; BAT3, B-associated transcript 3; BTLA, B- and T-lymphocyte attenuator; CCR4, C-C chemokine receptor type-4; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte antigen-4; eomes, eomesodermin; ERK, extracellular signal-regulated kinase; FOXO1, forkhead box protein O1; GATA3, GATA binding protein 3; GITR, glucocorticoid-induced TNFR-related protein; HLA, human leukocyte antigen; HVEM, herpes virus entry mediator; ICOS, T-cell costimulator; JAK, janus kinase; LAG-3, lymphocyte activation gene 3; LAIR1, leukocyte-associated immunoglobulin receptor 1; LFA-1, leukocyte function-associated antigen 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor κB; NRP1, neuropilin-1; PD-1, programmed cell death protein 1; PI3K-AKT, phosphatidylinositol 3-kinase-protein kinase B; PLC, phospholipase C; RAS, rat sarcoma virus; SLAM, signaling lymphocytic activation molecule; STAT, signal transducer and activators of transcription; syk, spleen tyrosine kinase; T-bet, T-box expressed in T cells; TIGIT, T-cell immunoglobulin and ITIM domain; TIM, T-cell immunoglobulin and mucin domain; TRAF, tumor necrosis factor receptor-associated factor; VISTA, V-domain Ig suppressor of T-cell activation; ZAP70, ζ-chain-associated protein kinase 70.