Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Monopoiesis and Tumor-Associated Monocytes
3. Liver Macrophages and Their Plasticity in Response to the Tumor Microenvironment
4. The Role of Macrophages in HCC Pathogenesis
5. Macrophages in HCC Prognosis
6. The Potential Role of Macrophages in HCC Treatment
7. Critical Analysis of Data and Future Perspectives
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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---|---|---|---|
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Chen et al. (2016) [60] | Human | High level of infiltration of IL21+ TFH-like cells induces pro-tumorigenic M2b Mϕ polarization and HCC growth. | Fcγ receptor–TLR cross-talk is required for M2b Mϕ polarization and subsequent upregulation of the M2 markers IL10 and CCL1. |
Zhang et al. (2016) [89] | Human | CD169+ Mϕs could suppress tumor progression by enhancing CD8+ T-cell activity in human HCC. | Tumor-induced autocrine TGF-β downregulates CD169 expression by Mϕs. |
Zhang et al. (2018) [63] | Human/Animal | M1 Mϕs accumulate in the SPON2-abundant regions of HCC, exhibiting antitumor immune responses through distinct integrin-Rho GTPase-Hippo pathways. | SPON2 interactions with integrin α4β1 receptors activate RhoA and Rac1, resulting in F-Actin accumulation that promotes M1 Mϕ infiltration and migration. |
Zhao et al. (2012) [66] | Human | IL-6/STAT3 signaling pathway regulates Mϕ polarization in HCC, and its inhibition suppresses tumor formation and metastases. | The TME induces the formation of suppressive MΦs, leading to early T cell activation and subsequent MΦ IDO expression in HCC. |
Zhang et al. (2018) [75] | Human/Animal | M2 Mϕs under FAO-mediated upregulated secretion of IL-1β enhance the proliferation, migration and invasion of HCC cells. | IL-1β induction is reactive oxygen species-dependent and NLRP3-dependent. |
Schneider et al. (2012) [77] | Animal | Chemically induced hepatocarcinogenesis triggers an intrahepatic accumulation of macrophages and cytotoxic T cells. | Activation of adaptive immunity-related pathways affect survival of patients with HCC. |
Mano et al. (2013) [78] | Human/Animal | TAMs correlate with pSTAT3 expression in HCC, expressing high levels of IL-6. | IL-6 stimulates cell proliferation and the migration of human HCC cell lines. |
Guo et al. (2017) [81] | Human | The expression of CD68, CD163 and CD206, the M2-TAM markers, is significantly higher in HCC tissues than in normal hepatic tissues. | IL-17 expression by M2-TAMs is augmented by oxaliplatin treatment and reduces oxaliplatin-induced apoptosis in HCC cells by activating CMA. |
Bartneck et al. (2019) [90] | Animal | Pro-inflammatory CCR2+ TAMs accumulate at the highly vascularized HCC border, whereas CD163+ immune-suppressive TAMs accrue in the HCC center. | CCR2+ M2 Mϕs express CCL6, which is involved in immune cell recruitment, and NF-κB, which is associated with many inflammatory processes. |
Zhang et al. (2018) [85] | Human/Animal | M2 Mϕs enhance IL-1β secretion in HCC under moderate hypoxic conditions via an HIF-1α/IL-1β signaling loop, leading to increased metastasis and the poor prognosis of HCC patients. | TLR4/TRIF/NF-κB signaling mediates cell necrotic debris–induced IL-1β production by macrophages, inducing an epithelial–mesenchymal transition in HCC cells. |
Zang et al. (2018) [88] | Human/Animal | Liver inflammatory macrophages of HBV-related HCC patients produce high amounts of IL-23, which in turn augment macrophage-induced angiogenesis in the JAK-STAT3 pathway. | Blocking IL-23 cytokine activity decreased liver cancer development in the murine model. |
Wang et al. (2017) [69] | Human | M2 Mϕs promote HCC progression by secreting cytokine factor CCL18. | CTGF is the key factor secreted by mesenchymal-like HCC cells that leads to the polarization of Mϕs, promoting HCC progression. |
Study (Year) | Study Subjects | Primary Outcome | Secondary Outcome |
---|---|---|---|
Ke et al. (2019) [97] | Human/Animal | ΜiR-148b deficiency promotes HCC growth and metastasis through CSF1/CSF1R-mediated TAM infiltration. | Decreased miR-148b levels and increased TAM infiltration were correlated with worse prognoses for HCC patients. |
Chen et al. (2019) [98] | Human/Animal | The levels of PFKFB3 + CD68+ cell infiltration in peritumoral tissues were negatively correlated with the overall survival and could serve as an independent prognostic factor for survival in patients with HCC. | Tumor-derived soluble factors upregulated PFKFB3 in TAMs, which in turn mediated the increased expression of PD-L1 by the activation of the NF-kB signaling pathway. |
Li et al. (2019) [99] | Human/Animal | SIRT4 is downregulated in CD68+ M2-like TAMs and correlates with the poor survival of HCC patients. | Downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. |
Zhang et al. (2016) [100] | Human | High peritumoral HMGB1 expression and TAM count, which correlated positively with tumor size and the BCLC stage of HCC, are independent prognostic factors for OS and RFS. | The degree of TAM infiltration is higher in peritumoral tissues with high HMGB1 expression than in peritumoral tissues with low HMGB1 expression. |
Kono et al. (2016) [102] | Human | M-CSF density, CD163 index and CD31 index in peritumoral tissues are independent prognostic factors HCC patients. | M-CSF, M2 Mϕs and angiogenesis in the peritumoral liver tissue are correlated with DFS after surgery. |
Ohno et al. (2014) [103] | Human/Animal | Increased intratumoral infiltration of CD204-positive or MCT4-positive macrophages suggested shorter OS in patients with HCC. | MCT4+ HCC cases correlated with higher intratumoral M2-Mϕ and higher intratumoral MCT4-positive Mϕ. |
Zhu et al. (2008) [105] | Human/Animal | High peritumoral M-CSF and Mϕs are associated with HCC progression, disease recurrence and poor survival after hepatectomy. | High peritumoral M-CSF and Mϕ density correlate with large tumor size, presence of intrahepatic metastasis and advanced stage. |
Zhu et al. (2014) [106] | Human | OPN, combined with PTMs, is an independent prognostic factor for both OS and TTR of early-stage HCC after curative resection. | PTM expression is closely associated with tumor recurrence and survival in HCCs with higher OPN levels, but is not significant in those with lower OPN expression. |
Study (Year) | Study Subjects | Outcome |
---|---|---|
Zhang et al. (2010) [109] | Animal | Depletion of macrophages by clodrolip or zoledronic acid, in combination with sorafenib, significantly inhibited HCC progression, angiogenesis and lung metastasis compared with the use of sorafenib alone. |
Wu et al. (2019) [110] | Animal | Sorafenib, at a subpharmacologic level, augments the antitumor effects of mCAR-T cells, by promoting IL12 secretion in TAMs. |
Sprinzl et al. (2013) [111] | Animal | Sorafenib triggers the proinflammatory activity of TAMs and subsequently induces antitumor NK cell responses in a cytokine- and NF-κB-dependent fashion. |
Yao et al. (2017) [113] | Animal | The natural CCR2 antagonist 747 elevates the number of CD8+ T cells in HCC by blocking TAM-mediated immunosuppression and inhibiting HCC progression in a CD8+ T-cell-dependent manner. |
Yang et al. (2012) [116] | Animal | E2 suppresses macrophage alternative activation and, as a result, HCC progression, by keeping ERβ away from interacting with ATP5J, thus inhibiting the JAK1-STAT6 signaling pathway. |
Tsuchiyama et al. (2008) [117] | Animal | Recombinant adenovirus vector expressing MCP-1 enhances the antitumor effects of suicide gene therapy against HCC by M1 macrophage activation. |
Guerra et al. (2017) [118] | Animal | Hydrogel-embedded M1 macrophages upregulate nitrite and TNF-α, activating caspase-3-induced apoptosis and HCC regression. |
Xiao et al. (2015) [120] | Animal | Macrophage phagocytosis of HCC cells is increased after treatment with CD47 antibodies that block CD47 binding to SIRPα. |
Tan et al. (2016) [121] | Animal | IRE1α inhibition by genipin on TAMs reduces XBP-1 splicing and NF-κB activation, suppressing HCC proliferation. |
Wang et al. (2019) [122] | Animal | Co-delivery of glycyrrhizin and doxorubicin attenuates the activation of macrophages and their phagocytic activity, enhancing the therapeutic efficacy for HCC. |
Sprinzl et al. (2015) [112] | Animal | Sorafenib lowers mCD163 and IGF-1 release by M2 macrophages, decelerating M2-macrophage-driven HepG2 proliferation. |
Deng et al. (2016) [114] | Human/Animal | Sorafenib abolished polarized-macrophage-induced EMT and migration of HCC cells in vitro and also attenuated HGF secretion in polarized macrophages, decreasing plasma HGF in patients with HCC. |
Wei et al. (2015) [115] | Animal | Sorafenib inhibited miR-101 expression, enhanced DUSP1 expression and lowered TGF-β and CD206 release in M2 cells, slowing macrophage-driven HCC. |
Li et al. (2018) [123] | Animal | In mice with HCC, injection of LipC6 reduces the number of TAMs, their production of ROS and their ability to suppress the anti-tumor immune response. |
Yin et al. (2014) [125] | Animal | nsPEFs enhance HCC cell phagocytosis by human macrophage cell (THP1) in vitro. |
Chen et al.(2014) [124] | Animal | In vivo, low doses and multiple treatments of nsPEF significantly elevate macrophage infiltration in HCC tumors, contributing to tumor ablation. |
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Arvanitakis, K.; Koletsa, T.; Mitroulis, I.; Germanidis, G. Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy. Cancers 2022, 14, 226. https://doi.org/10.3390/cancers14010226
Arvanitakis K, Koletsa T, Mitroulis I, Germanidis G. Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy. Cancers. 2022; 14(1):226. https://doi.org/10.3390/cancers14010226
Chicago/Turabian StyleArvanitakis, Konstantinos, Triantafyllia Koletsa, Ioannis Mitroulis, and Georgios Germanidis. 2022. "Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy" Cancers 14, no. 1: 226. https://doi.org/10.3390/cancers14010226