Macrophages in Liver Cancer

Macrophages and Liver Cancer

As one of the leading lethal cancers worldwide, liver cancer, also named hepatocellular carcinoma (HCC), is an inflammation-associated cancer. Liver cancer is caused by different etiological factors such as hepatitis virus, non-alcoholic steatohepatitis and alcohol. The tumor microenvironment (TME) plays a key role in the initiation and progression of liver cancer. TME promotes liver cancer cell to acquire abnormal phenotypes and recruits immune cells, such as macrophages and T cells. Tumor-associated macrophages (TAMs) are a well-known component of the TME, which take part in cancer progression and metastasis. TAM abundantly infiltrates TME and is often associated with the poor prognosis of patients with liver cancer. The important roles of TAMs include immunosuppressive function, enhancement of cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), and maintenance of stemness. Therefore, targeting TAMs might be critical for developing an effective therapy for liver cancer.

Origin and Heterogeneity of Liver macrophages

As one of the definitions, liver macrophages are composed of Kupffer cells and monocytes. Kupffer cells are self-sustaining, non-migratory tissue-resident phagocytes and originate from yolk sac-derived precursors during embryogenesis. Since Kupffer cells are immunogenic and receive signals from the local microenvironment, Kupffer cells are essential for hepatic and systemic homeostasis. Following their activation by danger signals, Kupffer cells modulate inflammation and recruit immune cells to the liver.

However, the definition above is inadequate as macrophages have several origins during ontogeny and each of these different lineages persists into adulthood. Other functional classifications that include binary inflammatory states are more often used. In those classifications, macrophages can be induced two distinct polarization phenotypes, the classically activated M1 and the alternatively activated M2 macrophages. The two polarization phenotypes have almost contrarious functions on each other. By now, the actual mechanism of macrophage polarization is entirely unclear because of the intense crosstalk between macrophage polarization and the microenvironment.

Fig.1 Macrophages origin and heterogeneity.^1,3

Role of Macrophages in Pathogenesis of Liver Cancer

• TAMs promote cancer cell proliferation, invasion, and metastasis

M2 macrophages have been shown to play an essential role in promoting cancer cell migration in HCC via the TLR4/STAT3 signaling pathway. Aberrant activation of the NTS/IL-8 pathway plays a pro-tumorigenic role in the inflammatory microenvironment of HCC. IL-6 derived by macrophages can induce epithelial-mesenchymal transition (EMT) of HCC cells, and promote HCC invasion and metastasis. Moreover, CXCL8 produced by activated macrophages increases the expression of miR-17 cluster in HCC cells and promotes HCC progression and metastasis.

• TAMs promote angiogenesis and cancer cell stemness

TAMs have been demonstrated to produce a variety of angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and several matrix metalloproteinases (MMPs). The high heterogeneity and malignancy of liver cancer are partly attributed to cancer stem cells (CSCs), which promote tumor recurrence, metastasis, and development of resistance to therapies. TAMs have been suggested to promote CSC-like properties via various signaling pathways, such as TGF-β signaling pathway and Wnt/β-catenin signaling pathway.

• TAMs promote autophagy

Mounting evidence suggests the importance of autophagy in the regulation of the function of TAMs and antitumor immunity [91]. Studies have shown that autophagy-deficient Kupffer cells promoted liver fibrosis, inflammation, and hepatocarcinogenesis. Moreover, baicalin can inhibit live cancer development and progression by repolarizing TAM towards the M1 phenotype via autophagy-associated activation of RelB/p52.

• TAMs modulate therapeutic resistance

The orally administrated multikinase inhibitor sorafenib shows limited efficacy in HCC patients due to the development of intolerance and resistance. TAM has been demonstrated to induce immunosuppression and weaken the efficacy of sorafenib in HCC [97]. Moreover, oxaliplatin-based chemotherapies are widely used in patients with advanced HCC. It has been reported that TAMs are important drivers of resistance to oxaliplatin by trigging autophagy and apoptosis evasion in HCC cells. The density of TAMs in HCC samples has been associated with the efficiency of transarterial chemoembolization in HCC.

Fig.2 Therapeutic strategies targeting TAMs in HCC.^2,3

Macrophage-targeting Therapies in Liver Cancer

Increasing evidence suggests the critical roles of TAMs in the development and progression of liver cancer. Hence, immunotherapies targeting TAMs have emerged as a promising approach to treat patients with liver cancer. The current therapeutic strategies targeting TAMs include phagocytosis-promoting therapies, inhibition of monocyte recruitment, elimination of pre-existing TAMs in the tumor tissue, reprogramming TAM polarization, and neutralizing pro-tumorigenic factors secreted by TAMs.

Table 1 Agents targeting TAMs for the treatment of liver cancer. (Huang, 2021)

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References

1. Tian, Zhiqiang, et al. "Macrophages and hepatocellular carcinoma." Cell & bioscience 9 (2019): 1-10.
2. Huang, Yu, et al. "The role of tumor associated macrophages in hepatocellular carcinoma." Journal of Cancer 12.5 (2021): 1284.
3. Under Open Access license CC BY 4.0, without modification.