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.
Highlights
Chronic liver injury progressively causes liver diseases, including nonalcoholic fatty liver disease (NAFLD), via excessive production of the extracellular matrix (ECM), which drives fibrosis and cirrhosis and results in hepatocellular carcinoma (HCC) [1]
The levels of laminins and pY705STAT3 (Fig. 1E), collagen I, α-smooth muscle actin (SMA), laminins, laminin γ2, and transmembrane 4 L six family member 5 (TM4SF5) expression levels were elevated in FVB/N-TgTM4SF5 mice compared with age-matched WT mice, in addition to CD34, AFP, α-l-fucosidase [FUCA (AFU)], which are HCC markers [29,30,31], hepatic damage, and collagen I deposition (Fig. 1F)
Immunostaining of liver tissues from HCC patients showed substantially elevated levels of TM4SF5, laminins, collagen I, and pY705STAT3 in peritumoral and tumor regions compared with normal regions (Fig. 2A)
Summary
Chronic liver injury progressively causes liver diseases, including nonalcoholic fatty liver disease (NAFLD), via excessive production of the extracellular matrix (ECM), which drives fibrosis and cirrhosis and results in hepatocellular carcinoma (HCC) [1]. The identification of cancer-associated antigens by APCs leads to T-cell priming and tumor infiltration, which eventually leads to T-cell-mediated recognition and killing of the tumor cells [3] During this process, immune checkpoints, such as cytotoxic T lymphocytic protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), on immune cell surfaces have been actively targeted to boost the immune system and for anti-tumor immunotherapies [4]. NK cell-mediated cytotoxicity relies on “missing-self” and “induced-self” recognition to identify target cancer cells by maintaining a precise balance between co-stimulatory and co-inhibitory signals via functional receptors. These interacting signals eventually lead to the activation and functional status of NK cells [11]. We currently have a good understanding of the complex and often redundant activation/inactivation pathways of NK cells [13], HCC-specific checkpoints in hepatocytes and NK cells warrant further investigation
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