The Role of Tumor Associated Macrophages in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and represents a classic paradigm of inflammation-related cancer. Various inflammation-related risk factors jointly contribute to the development of chronic inflammation in the liver. Chronic inflammation, in turn, leads to continuous cycles of destruction-regeneration in the liver, contributing to HCC development and progression. Tumor associated macrophages are abundant in the tumor microenvironment of HCC, promoting chronic inflammation and HCC progression. Hence, better understanding of the mechanism by which tumor associated macrophages contribute to the pathogenesis of HCC would allow for the development of novel macrophage-targeting immunotherapies. This review summarizes the current knowledge regarding the mechanisms by which macrophages promote HCC development and progression, as well as information from ongoing therapies and clinical trials assessing the efficacy of macrophage-modulating therapies in HCC patients.

Keywords: Hepatocellular carcinoma; Immunotherapy; Tumor associated macrophage; Tumor microenvironment.

Figure 1

Origin and classification of liver macrophages. Liver macrophages, consisting of Kuffer cells and monocyte-derived macrophages, play essential roles in sustaining hepatic and systematic homeostasis. Myeloid cells including blood monocytes, scan the liver vasculature and eventually derive macrophages infiltrating into the liver. Kuffer cells are resident phagocytes originating from yolk sac-derived precursors during embryogenesis. Macrophages can be classified into two distinct functional phenotypes according to their responses to different environmental stimuli in vitro. M1 macrophages are induced by LPS, IFN-γ, and GM-CSF. They secrete the pro-inflammatory cytokines IL-1α/β, IL-12, IL-18, iNOS, and TNF-α, as well as promoting the function of effector T cells. M2 macrophages are induced by IL-4, IL-10, IL-13, and glucocorticoids, and exert anti-inflammatory and immune-regulatory effects by expressing IL-10, Arg1, and PD-L1.

Figure 2

Effects of TAMs in the pathogenesis of HCC. TAM can promote HCC development and progression via multiple mechanisms, including promoting cancer cell proliferation, stemness, invasion, and metastasis, modulating angiogenesis, autophagy, drug resistance, as well as weakening the functions of NK cells and effector T cells, etc.

Figure 3

Therapeutic strategies targeting TAMs in HCC. The development of TAM-targeting immunotherapeutic strategies includes induction of phagocytosis, inhibition of monocyte recruitment, elimination of pre-existing TAMs, reprogramming of macrophage polarization, and neutralization of the pro-tumorigenic factors secreted by TAMs.