Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis

BACKGROUND AND AIMS: Lysyl oxidase‐like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis. APPROACH AND RESULTS: Here, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline‐deficient, l‐amino acid–defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD‐L1) expression, which further suppressed the function of CD8(+) T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T‐cell transfer or PD‐L1 neutralization. Label‐free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)‐mediated signal transducer and activator of transcription–dependent PD‐L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN‐mediated PD‐L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68(+) cells was positively correlated with PD‐L1 level. High expression of LOXL4 in CD68(+) cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC. CONCLUSIONS: LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.