Macrophages and hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers in the human population. HCC is an inflammation-associated cancer caused by different etiological factors. The chronic inflammation leads to continuous cycles of hepatocytes destructive-regenerative process and contributes to HCC initiation and progression. Macrophages play a crucial role in chronic liver inflammation. The tumor microenvironment plays a key role in the progression of HCC. Tumor-associated macrophages are a well-known component of the tumor microenvironment and abundantly infiltrate HCC microenvironment. The roles of macrophages in the development and progression of HCC have been recognized. The deep understanding of macrophages in HCC will be critical for developing effective HCC therapy. Targeting of macrophages might provide novel therapeutic approaches for HCC patients and is an emerging field of interest. This review summarizes the knowledge on the contribution of macrophages in the development and progression of HCC, as well as potential immunotherapy being explored in targeting macrophages.

Keywords: Hepatocellular carcinoma; Immunotherapy; Macrophage; Tumor microenvironment.

Fig. 1

Macrophages origin and heterogeneity. Macrophages are the end cells of the mononuclear lineage. Erythromyeloid progenitors from yolk sac and fetal liver and HSCs from bone marrow develop into the progenitor of macrophages. Macrophages can be induced two distinct polarization phenotypes according to the spectrum of their responses by different microenvironmental stimuli. M1 macrophages exert cytotoxic function by releasing IL-1α, IL-1β, IL-12, IL-18, iNOS, and TNF-α which are induced by LPS, IFN-γ and GM-CSF. M2 macrophages exert anti-inflammatory activities by express low IL-12, high IL-10, arginase 1 and PD-L1 which are induced by IL-4, IL-10, IL-13, M-CSF and helminth. Arg-1, arginine-1; HSCs, hematopoietic stem cells; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-γ; LPS, lipopolysachharide; GM-CSF, granulocyte–macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; TNF-α, tumor necrosis factor α

Fig. 2

TAMs-targeted strategies in hepatocellular carcinoma. These strategies can be roughly divided into those: (i) inhibition of monocytes recruitment; (ii) eliminating TAMs already present in tumor tissue; (iii) functionally re-educating TAMs polarization; (iv) neutralizing the tumor-promoting products of TAMs