Tumor‑associated macrophages activated in the tumor environment of hepatocellular carcinoma: Characterization and treatment (Review)

Abstract

Hepatocellular carcinoma (HCC) tissue is rich in dendritic cells, T cells, B cells, macrophages, natural killer cells and cellular stroma. Together they form the tumor microenvironment (TME), which is also rich in numerous cytokines. Tumor‑associated macrophages (TAMs) are involved in the regulation of tumor development. TAMs in HCC receive stimuli in different directions, polarize in different directions and release different cytokines to regulate the development of HCC. TAMs are mostly divided into two cell phenotypes: M1 and M2. M1 TAMs secrete pro‑inflammatory mediators, and M2 TAMs secrete a variety of anti‑inflammatory and pro‑tumorigenic substances. The TAM polarization in HCC tumors is M2. Both direct and indirect methods for TAMs to regulate the development of HCC are discussed. TAMs indirectly support HCC development by promoting peripheral angiogenesis and regulating the immune microenvironment of the TME. In terms of the direct regulation between TAMs and HCC cells, the present review mainly focuses on the molecular mechanism. TAMs are involved in both the proliferation and apoptosis of HCC cells to regulate the quantitative changes of HCC, and stimulate the related invasive migratory ability and cell stemness of HCC cells. The present review aims to identify immunotherapeutic options based on the mechanisms of TAMs in the TME of HCC.

Keywords: hepatocellular carcinoma; immunotherapy; tumor microenvironment; tumorigenesis; tumor‑associated macrophages.

Figure 1

Classical macrophage phenotypes. Macrophages have M1, M2, M3, M4, M(Hb) and Mox polarization phenotypes. The M1 and M2 phenotypes are the two main macrophage polarization phenotypes. M3 macrophages are an intermediate phenotype that bridges the interconversion between M1 and M2 macrophages. Macrophages are referred to as TAMs in the tumor microenvironment. TAMs can also be divided into M1 and M2 subtypes. Pre-tumor macrophages polarize to the M1 subtype and inhibit tumorigenesis and progression, while more macrophages polarize to the M2 subtype in the later stages and exert pro-tumorigenic effects. M1 macrophages are mainly induced by LPS and IFN-γ. M2 macrophages are stimulated by different regulatory factors and differentiate into four subtypes: M2a, M2b, M2c and M2d. IL-4 and CCL22 are responsible for M2a macrophage polarization, and M2a macrophages focus on tissue remodeling and reducing inflammation. Fc-γ receptor and LPS/IL-1β cause M2b macrophage polarization, and M2b macrophages serve a role in antigen presentation and promoting HCC progression. M2c macrophages are polarized by TGF and IL-10 and have functions in matrix deposits and immunoregulation. TLR and IL-6 drive M2d macrophage polarization, and M2d macrophages contribute to angiogenesis, and tumor growth and progression. CXCL4 can drive macrophage polarization toward the M4 phenotype. In Hb and OxPL pathological tissue, macrophages are polarised to M(Hb) and Mox, respectively. CCL22, C-C motif chemokine ligand 22; CXCL4, chemokine C-X-C motif ligand 4; M(Hb), hemoglobin-stimulated macrophage; HCC, hepatocellular carcinoma; LPS, lipopolysaccharide; OxPL, oxidized phospholipid; TAMs, tumor-associated macrophages; TLR, toll-like receptor.

Figure 2

Direct modulation of the HCC tumor microenvironment by TAMs. Molecular mechanisms by which TAMs affect HCC cells. M1 TAMs mainly act to control hepatocarcinogenesis. M2 TAMs can enable faster adaptation of HCC cells to the tumor microenvironment through activation of multiple complexes and signaling pathways in HCC cells. AGER, advanced glycosylation end-product specific receptor; CCL17, C-C motif chemokine ligand 17; CCL22, C-C motif chemokine ligand 22; CCR4, C-C motif chemokine receptor 4; HCC, hepatocellular carcinoma; JAK, Janus kinase; miR, microRNA; PD-L1, programmed death ligand 1; RAGE, receptor for advanced glycation endproducts; S100A4, S100 calcium binding protein A4; S100A9, S100 calcium binding protein A9; SIX1, sine oculis homeobox homolog 1; TAMs, tumor-associated macrophages; TGFBR2, TGF-β type II receptor gene; TLR4, toll-like receptor 4; TNFR1, TNF receptor superfamily member 1A.

Figure 3

Role of TAMs in promoting angiogenesis of HCC. The indirect regulation of HCC tissues by TAMs mainly lies in the suppression of immune system function and pro-angiogenesis. In terms of angiogenesis, TAMs receive stimulation from HIF-1α in the tumor microenvironment, and act on endothelial cells and mediate tumor angiogenesis via S100, VEGF, Ang1 and Ang2. Ang, angiopoietin; HCC, hepatocellular carcinoma; HIF-1α, hypoxia-inducible factor-1α; TAM, tumor-associated macrophage.

Figure 4

Role of TAMs in regulating the immune environment of HCC cells. Macrophages mainly regulate the immune environment by modulating CD8⁺ cells, thereby promoting tumor growth. TAMs not only target CD8⁺ cells through iNOS, PD-1 and granzyme B, but also through cytokines and proteins such as B7 molecules, IDO, IL-10 and TGF-α to regulate NK cells and CD4⁺ Th2 cells. Furthermore, secretions of TAMs act on CD4⁺ Th1 cells, which are helper cells for the immune function of CD8⁺ T cells, to block the immune activity of CD8⁺ cells. The dotted lines indicate the functional inhibition of CD4⁺ Th1 cells by TGF-β and IL-10. HCC, hepatocellular carcinoma; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; NK, natural killer; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand 1; TAM, tumor-associated macrophage; Th, T helper; Treg, regulatory T cell.

Figure 5

Treatment of HCC targeting TAMs. Targeting the infiltrated TAMs and their polarized subtypes: i) Removal of TAMs that already exists; and ii) inhibition of monocyte/macrophage recruitment. Restoration of tumor-resistant effects of TAMs: i) Inhibition of the polarization pathway from monocytes to M2 TAMs; ii) regulation of TAM polarization; and iii) reprogramming of TAM products. Inhibition of immune escape in HCC. HCC, hepatocellular carcinoma; TAM, tumor-associated macrophage.