Table 1.
TAMs and MDSCs in HCC: phenotypes, functions, clinical and pathological associations.
| Murine HCC models | Presence / Generation |
Identification / Marker | Effects associated with the presence of TAMs or MDSCs |
Refs |
|---|---|---|---|---|
| Md2-KO mouse, inflammation-induced HCC | TAMs detected in tumors | Morphology | TAM-derived TNF-α activates hepatocyte NF-κB and promote HCC | 12 |
| DEN driven HCC model | TAMs detected in tumors | Isolation by centrifugation | TAM-derived TNF-α and IL-6 activates NF-κB and C/EBPβ, and promote HCC | 13,14 |
| DEN driven HCC model | TREM-1-expressing TAMs detected in liver | F4/80+ CD11b+ Ly6G− Ly6C− | TAM activation and TAM-derived proinflammatory cytokines IL-6, IL-1b, TNF, CCL2 and CXCL10 promote DEN driven HCC; the myeloid cell surface receptor TREM-1 expressed by TAMs is crucial in the development of HCC. | 15 |
| Nude mice bearing orthotopic HCC tumors | TAMs increased in tumors following sorafenib treatment | F4/80+ and CD11b+ by IHC and FACS | Depletion of TAMs by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with sorafenib alone | 19 |
| Nude mice bearing orthotopic HCC tumors (SMMC7721, HCCLM3) | TAMs increased in tumors with high metastatic properties | F4/80+ by IHC | Depletion of TAMs using clodrolip dramatically decreased FoxQ1-enhanced HCC metastasis | 32 |
| Abcb4 knockout mice mimicking cholangitis-associated HCC | TAMs observed at the invasive front of HCC | F4/80+ by IF | TAMs were the major source of MMP-9 at the invasive front of HCC, and could be involved in the matrix remodelling and HCC invasion. | 29 |
| Orthotopic and ectopic mouse models with mouse HCC cell lines | TAMs detected in tumors | CD68+ CD206+ by IHC and FACS | TAMs link with HCC gender disparity. Estrogen could suppress HCC progression through inhibiting TAMs function, including reducing arginase activity, mannose receoptor CD206 expression and IL-10 production. This is dependent on JAK1-STAT6 signaling pathway. | 63 |
| Hepa1-6 mouse HCC cell line | TAMs generated in vitro by culturing RAW 264.7 with IL-4 for 24 h | Macrophage lines | Conditioned media from RAW 264.7 treated with IL-4 but not LPS plus IFNγ increased CSC-like properties and EMT of Hepa1-6 cells through TGFβ1 | 34 |
| Subcutaneous and Orthotopic mouse models with HCC cell lines; DEN driven HCC model; MYC-expressing spontaneous HCC model. | MDSCs observed but differs depending on the mouse models | CD11b+ Gr-1+ | In subcutaneous and orthotopic tumors, MDSCs increased systemically. In DEN driven and MYC-expression tumors, MDSCs only accumulate in the livers of mice with advanced HCC. KC and GM-CSF controlled MDSC frequency. | 16 |
| HCC patients |
Presence / Generation |
Identification / Marker |
Effects associated with the presence of TAMs or MDSCs |
Refs |
| HCC patients TMA | High density of TAMs in the peritumoral liver tissue | CD68+ by IHC | Peritumoral TAMs correlates with large tumor size, intrahepatic metastasis, high TNM stage and poor survival | 24 |
| Paraffin-embedded tissue from HCC patients | TAMs detected in tumors | CD68+ by IHC | High density of TAMs was related to increased intratumoral Treg; TAMs-increased Treg was partially blocked by anti-IL-10 antibody. | 45 |
| Tumors from HCC patients | TAMs detected in tumors | CD14+ by FACS and CD68+ by IHC | TAM galectin-9 binds to T cell TIM-3, which induced senescence of effector T cells. | 40 |
| Tumors and peripheral blood samples from HCC patients | TAMs detected in tumors | CD14+ by FACS and CD68+ by IHC | TAMs-derived IDO impaired T cell proliferation and effector cytokine production. | 47 |
| Tumors from HCC patients, peripheral blood samples from healthy donors. | TAMs detected in tumors | CD14+ HLA-DR+ by FACS and CD68+ by IHC | TAM B7-H1 binds to T cell PD-1, which suppress effector T cell function. | 5,49 |
| Tumors and xenograft tumors from HCC patients, HepG2 human HCC cell line | TAMs detected in tumors | CD14+ by FACS | TAMs enhanced human HCC CSCs phenotype through TAMs-derived IL-6 and its downstream activation of STAT3 signaling in HCC. | 36 |
| HCC patients peripheral blood and tumor | TEMs increased in HCC patients | CD14+CD16+TIE2+ by FACS and IF | TIE2-expressing monocytes/macrophages correlate with micro-vessel density and could serve as diagnostic marker | 23 |
| HepG2 human HCC cell line | Activated Macrophage lines (RAW 264.7, THP-1, mouse peritoneal macrophages) | Macrophage lines | Conditioned media from macrophages from various sources activated by PMA or LPS but not IFNγ increased the migration and invasiveness of HepG2 cells by destabilizing the adherens junction in vitro | 33 |
| Tumors and peripheral blood samples from HCC patients | MDSCs increased in peripheral blood and tumors of HCC patients | CD14+ HLA-DR−/low Arginasehigh | MDSCs induced regulatory T cells and inhibited tumor-specific T-cell activation | 7 |
| Peripheral blood samples from HCC patients | MDSCs increased in HCC patients | CD14+ HLA-DR−/low | MDSCs inhibited autologous NK cell cytotoxicity and cytokine secretion in vitro. This is dependent on cell contact and NKp30 on NK cells, but not on arginase activity of MDSCs. | 56 |
| Peripheral blood samples from HCC patients | MDSC increased in HCC patients | CD14− HLA-DR− CD33+ CD11b+ | Augmented Tregs, MDSC, PD-1+–exhausted T cells and immunosuppressive cytokines (IL-10, TGFβ1) in patients with HCC. Depletion of Tregs, MDSC, PD-1+ T cells restored effector T cell function in vitro. | 9 |
See text for abbreviation