Table 3.
A summary of molecular targets in the tumor immune microenvironment of HCC.
| Target cell | Molecule | Major effects | Therapeutic strategy | Reference |
|---|---|---|---|---|
| MDSC | CCL26 | CCL26 mediates MDSC recruitment in the hypoxic regions of HCC. | CCL26 blockade | (39) |
| CCL9/CCR1 | CCL9/CCR1 induces MDSCs recruitment to the spleen. | CCL9/CCR1 blockade | (243) | |
| ENTPD2/CD39L1 | HIF-1 prompts MDSC accumulation via ENTPD2/CD39L1 in HCC. | ENTPD2/CD39L1 blockade | (40) | |
| CCRK | CCRK induction drives mTORC1-dependent G-CSF expression to recruit MDSCs and enhance tumorigenicity in HCC. | Anti-CCRK | (244) | |
| IL-6 | IL-6 expression level is highly associated with MDSC phenotype in HCC patients. | Anti-IL-6 | (245) | |
| PD-L1 | PD-L1+ MDSCs are increased in HCC patients. | PD-L1 blockade | (246) | |
| C5AR | C5AR can recruit MDSCs to the TIME. | C5AR blockade | (240) | |
| Treg | PD-1 | PD-1-mediated inhibitory signal in the TME. | PD-1 blockade | (247, 248) |
| CTLA-4 | Tumor-induced regulatory DC subset inhibit immunity via CTLA-4-dependent IL-10 and IDO production. | CTLA-4 blockade | (75, 249) | |
| TIM3 | Antibodies against TIM3 restore immune response of HCC-derived T cells to tumor-specific antigens. | TIM3 blockade | (97, 250) | |
| LAG3 | Antibodies against LAG3 restore immune response of HCC-derived T cells to tumor-specific antigens. | LAG3 blockade | (97) | |
| GITR | GITR-ligation can improve anti-tumor response by abrogating Treg-mediated suppression in HCC. | GITR blockade | (251) | |
| ICOS | ICOS+ FOXP3+ Treg cells are enriched in the HCC TME. | ICOS blockade | (252) | |
| CCR4 | Tregs can be targeted and depleted by mABs towards CCR4. | Anti-CCR4 | (253) | |
| TGF-β | TGF-β prompts Treg infiltration into the liver. | Sorafenib | (54) | |
| TAM | IL-6, IL-23, IL-β, TNF-α | Cytokines enhance the expansion of IL-17-producing CD4+ Th17 cells. | Anti-IL-6, anti-IL-23, anti-IL-β, anti-TNF-α | (73, 254) |
| TGF-β | TGF-β prompts TIM-3 expression in TAMs. | Anti-TGF-β | (66) | |
| IL-1β | IL-1β prompts EMT and HCC immune escape. | Anti-IL-1β | (68) | |
| CCR2 | CCR2 prompts EMT transition and M2-plarization of TAMs. | Anti-CCR2 | (255, 256) | |
| CSF-1 | CSF-1 reprograms polarization of TAMs. | CSF-1 receptor antagonist | (257) |
MDSC, myeloid-derived suppressor cell; Treg, regulatory T; TAM, tumor-associated macrophage; HCC, hepatocellular carcinoma; TME, tumor microenvironment; TIME, tumor immune microenvironment; CCL26, C-C motif ligand 26; ENTPD2, endothelial growth factor; IDO, indoleamine 2, 3-dioxygenase; HIF, hypoxia-inducible factor; G-CSF, granulocyte-colony-stimulating factor; CSF, colony-stimulating factor; DC, dendritic cell; mAB, monoclonal antibody; TNF-α, tumor necrosis factor α; TGF-β, transforming growth factor β; EMT, epithelial-mesenchymal transition.