TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes

Abstract

Aberrant extracellular matrix and immune cell alterations within the tumor microenvironment promote the pathological progression of liver carcinogenesis. Although transmembrane 4 L six family member 5 (TM4SF5) is involved in liver fibrosis and cancer, its mechanism avoiding immune surveillance during carcinogenesis remains unknown. We investigated how TM4SF5-mediated signaling caused immune evasion using in vitro primary cells and in vivo liver tissues from genetic or chemically induced mouse models. TM4SF5-transgenic and diethylnitrosamine (DEN)-induced liver cancer mouse models exhibited fibrotic and cancerous livers, respectively, with enhanced TM4SF5, pY705STAT3, collagen I, and laminin γ2 levels. These TM4SF5-mediated effects were abolished by TM4SF5 inhibitor, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC). TM4SF5-dependent tumorigenesis involved natural killer (NK) cell exhaustion-like phenotypes including the reduction of NK cell number or function, which were blocked with TSAHC treatment. TM4SF5 expression in cancer cells downregulated stimulatory ligands and receptors for NK cell cytotoxicity, including SLAMF6, SLAMF7, MICA/B, and others. TM4SF5 suppression or inhibition reduced STAT3 signaling activity and recovered the receptor levels and NK cell surveillance, leading to reduced fibrotic and cancerous phenotypes, and longer survival. Altogether, these findings suggest that TM4SF5-mediated STAT3 activity for extracellular matrix modulation is involved in the progression of liver disease to HCC and that TM4SF5 appears to suppress NK cells during liver carcinogenesis.

TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases

“…Therefore, TM4SF5 appears to play important roles in the development of chronic liver disease. TM4SF5 is involved in the development of NASH [ 36 ], fibrosis [ 82 , 83 ], and HCC [ 13 , 56 ]. Compared with age-matched wild-type mice, 78-week-old TM4SF5-overexpressing transgenic mice (C57BL/6-TG TM4SF5 ) livers exhibit elevated immune cell infiltration, ballooned hepatocytes, and fibrotic phenotypes [ 36 ].…”

“…Furthermore, the pathological features for NASH associated with fibrosis in 78-week-old TG TM4SF5 mice show characteristics similar to those of human NASH patients, including ballooned hepatocytes, lipid accumulation, and immune cell infiltration during inflammation. Furthermore, one-year-old TM4SF5-overexpressing FVB/N-TG TM4SF5 mice show the formation of tumors in the liver, which are positive for AFP, FUCA, CD34, and laminin γ2 [ 13 ]. Together, these results suggest that TM4SF5 expression in hepatocytes is critically involved in the modulation of the inflammatory environment during conditions of chronic liver disease and malignancy progression ( Figure 3 ).…”

“…We recently reported that TM4SF5 plays a role in the communication between hepatocytes and MFs or NK cells, and the possible influence of this on the inflammatory microenvironment and immune system may lead to the development of NAFLD and HCC. These traits are also much more pronounced in the livers of Tm4sf5-expressing WT mice than in those of Tm4sf5 −/− knockout mice in methionine–choline-deficient diet-induced NASH mouse models [ 9 ] or in a diethylnitrosamine-induced HCC mouse model [ 13 ]. Regarding the roles of TM4SF5 in NASH and HCC development, in hepatocytes, TM4SF5 is involved in crosstalk with immune cells, in particular, macrophages (MFs) [ 9 ] and NK cells [ 13 ], which are critical for the development of an inflammatory environment in NASH or HCC associated with fibrosis.…”

“…TM4SF5 expression can be induced by inflammatory cytokines and can eventually lead to NASH in the presence of chronic metabolic abnormalities in the liver, frequently causing remodeling of the inflammatory environment through interactions with immune cells [ 9 , 13 ]. For example, TM4SF5-dependent bidirectional communication between macrophages and hepatocytes modulates the inflammatory environment during NASH progression [ 9 ].…”

“…For example, TM4SF5-dependent bidirectional communication between macrophages and hepatocytes modulates the inflammatory environment during NASH progression [ 9 ]. In addition, TM4SF5 overexpression downregulates costimulatory activation ligands in hepatocytes, which causes decreased cognate receptor expression on natural killer (NK) cells and eventually leads to the evasion of immune surveillance [ 13 ]. Thus, TM4SF5 may be a promising therapeutic target for the treatment of chronic metabolic liver diseases.…”