Table 1.
Dendritic cell, T cell and tumor-associated expression of B7/CD28 and TNFR superfamily ligands and receptors.
| Ligand(s) on DC | Receptor | Expression on Tumor Infiltrating Lymphocyte (TILs) or Tumors | Selected mAbs with FDA approval* or in actively recruiting clinical trials# | Beneficial Effects of Combination with Immune Checkpoint Blockade for DC Vaccination |
|---|---|---|---|---|
| CD80/86 | CTLA-4 (CD152) | • CTLA-4 expressed by activated T cells (56) |
Anti-CTLA-4 • Ipilimumab* • Tremelimumab# |
• CTLA-4 expressed on DC has a negative regulatory role (40) |
| PD-L1 (CD274)PD-L2 (CD273) | PD-1 (CD279) | • PD-1 and PD-L1 expressed by TILs and tumor cells (57) • Tumor expression of PD-L2 (58) |
Anti-PD-1 • Nivolumab* • Pembrolizumab* • Cemiplimab*Anti-PD-L1 • Durvalumab* • Atezolizumab* • Avelumab* |
• PD-1 blockade prolongs DC survival (47) • Reverse signaling via PD-L1/PD-L2 inhibits DC activation (52) |
| ICOS-L (CD275) | ICOS (CD278) | • ICOS expressed on TILs in CTLA-4 treated subjects (59) |
Agonist • GSK3359609# • MEDI-570# • JTX-2011# |
• Controls CD40L dependent antibody class-switching (60) |
| Galectin-9 | Tim-3 (CD366) | • Tim-3 expressed in TILs (61) |
Antagonist • MBG453# • TSR-022# |
• TIM-3 mediates uptake of necrotic antigens (62) • Increased TNF-α production when bound by galectin-9 (63) |
| MHC Class II | LAG-3 (CD223) | • LAG-3 expressed by TILs (64) |
Agonist BMS-986016# • TSR-033# • REGN3767# • IMP321# |
• sLAG-3-Ig enhances DC maturation and migratory chemokines (65). |
| CD40 | CD40L | • CD40 expressed in breast cancer (66), head and neck cancer (67) and melanoma (68) cells |
Agonist • APX005M • CDX-1140 • JNJ-64457107 R07009789/Selicrelumab |
• Licensing of DC to produce IL12p70 (21) |
| CD70 | CD27 | • CD27 constitutively expressed constitutively by T cells. • CD70 expressed in CLL (69) |
Antagonist • ARGX-110# • SGN-CD70A# |
• Important for T cell priming and memory responses (31) |
| OX40L (CD252) | OX40 (CD134) | • OX40 expressed by tumor infiltrating Tregs (70) | • MEDI6469# | • OX40-dependent Treg depletion by myeloid cell Fc receptor dependent ADCC (71) • Preferential induction of CD4+ T cell responses (72) |
| 4-1BBL | 4-1BB (CD137) | • 4-1BB inducibly expressed on T cells (73) • 4-1BB expressed on tumor cells (74) |
Agonist • PF-05082566/Utomilumab# • BMS-663513/Urelumab# |
• 4-1BB has anti-tumor effects (75) • Preferential induction of CD8+ T cell responses (75) |
Properties of B7/CD28 and TNSRF pathways which augment DC vaccination directly in addition to re-invigorating T cells.