Tumor-Associated Neutrophils in Hepatocellular Carcinoma Pathogenesis, Prognosis, and Therapy

Abstract

Hepatocellular carcinoma represents the most prevalent primary liver cancer worldwide, and it is either caused by intrinsic genetic mutations or by a multitude of extrinsic risk factors. Even though the interplay between chronic inflammatory changes and hepatocarcinogenesis has been at the forefront of clinical investigation for the past few decades, the role of tumor-associated neutrophils (TANs) in HCC development still remains ambiguous. On the one hand, N1 TANs exhibit an anti-tumorigenic activity, mediated by direct or indirect tumor cell lysis, whereas on the other hand, N2 TANs have been correlated with increased HCC growth, invasiveness, and metastasis. The association of an elevated Neutrophil-to-Lymphocyte Ratio (NLR) with poor prognosis in patients with HCC, has been recently brought into spotlight, consolidating its widespread use as a reliable biomarker. Due to the decisive involvement of TANs in HCC pathogenesis and development, the utilization of various neutrophil-centered anticancer treatment modalities has been under clinical experimentation, selectively targeting and modulating the processes of neutrophil recruitment, activation, and migration. This review summarizes current evidence on the role of TANs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting neutrophils.

Keywords: hepatocellular carcinoma; neutrophil-to-lymphocyte ratio; treatment resistance; tumor-associated neutrophils; tumorigenesis.

Figure 1

Activity of polarized N2 neutrophils in hepatocellular carcinoma. Peritumoral GM-CSF and CAFs modulate N2 neutrophils to an immunosuppressive profile, enhancing CD66b, PD-L1, TNF and CCL2 expression, alongside their capacity to suppress T cells. CAF-released CLCF1 drives the N2 polarization of TANs, induces CXCL6 and TGF-β production by tumor cells and promotes cancer stemness. N2 neutrophil-associated MMP-9 and oncostatin-M release promotes tumor neovascularization and enhances the metastatic potential of HCC. HCC: hepatocellular carcinoma; TAN: tumor-associated neutrophil; GM-CSF: granulocyte-macrophage colony-stimulating factor; TGFβ: tumor growth factor-β; TNF: tumor necrosis factor; PD-L1: programmed death-ligand 1; CXCL: C-X-C motif chemokine ligand; CCL2: C–C motif chemokine ligand 2; MMP-9: matrix metallopeptidase-9; CD66b: cluster of differentiation 66b; CAF: cancer-associated fibroblast; CLCF: cardiotrophin like cytokine factor.

Figure 2

Activity of polarized N1 neutrophils in hepatocellular carcinoma. N1 TANs exhibit ROS-mediated cytotoxic activity towards tumor cells, activate the innate and adaptive immune response, as well as enhance the spontaneous resolution of tumor-associated inflammation via the transmission of microRNA-223 to macrophages, hindering NLRP3 activity. TAN: tumor-associated neutrophil; NLRP3: NLR family pyrin domain containing 3; ROS: reactive oxygen species; DC: dendritic cell.