Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis

Abstract

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.

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

“…On the other hand, intercellular transfer of exosome-LOXL4 from HCC to human umbilical vein endothelial cells (HUVEC) promotes angiogenesis, as evidenced by increased HUVEC migration and tube formation [ 57 ]. More recently, Tan et al identified LOXL4 as a key factor in forming an immunosuppressive microenvironment for HCC [ 15 ]. The expression of LOXL4 was increased in a mouse model with liver carcinogenesis induced by a choline-deficient, L-amino acid-defined (CDAA) diet.…”

“…Specifically, LOXL4-harboring exosomes are primarily internalized in hepatic macrophages to shape an immunosuppressive phenotype, such as up-regulated programmed cell death 1 ligand 1 (PD-L1) expression, which further acts to suppress the activity of CD8 + T cells. The mechanism underlying the immunosuppressive role of LOXL4 on shaping macrophage phenotype lies in an H 2 O 2 -dependent activation of the interferon alpha and beta receptor subunit-1-signal transducer and activator of transcription 1 and 3-programmed death-ligand 1 (IFNAR1-STAT1/3-PD-L1) pathway [ 15 ]. The emerging role of LOXL4 in guiding the progression and modeling the microenvironment of HCC is summarized in Table 4 .…”

“…A growing body of evidence indicates that the expression of LOX family members increases in invasive and metastatic cancers, and their elevated expression correlates with poor survival [ 11 , 12 , 13 ]. Their crucial role in tumor proliferation, epithelial–mesenchymal transition (EMT), migration, invasion, formation of pre-metastatic niches, and immunomodulation have been well documented [ 11 , 14 , 15 , 16 , 17 ]. Consistent with these reports, we note that a genomic big data-centric pathway activity analysis reveals their role in the activation of the EMT pathway in cancer ( Figure 2 ).…”

Role of Exosomes in Immune Microenvironment of Hepatocellular Carcinoma

“…At the same time, exosomes derived from a variety of cells in the tumor microenvironment can regulate the loss of antitumor effects of CD8 + T cells. Both LOXL4 and miR-23a-3p derived from HCC cells can be delivered by exosomes and activate the expression of PD-L1 in hepatic macrophages after the exosomal internalization, thereby further inhibiting the function of CD8 + T cells or promoting their apoptosis [125,142].…”

Proteomics, Personalized Medicine and Cancer

“…Elevated levels of LOXL4 were found to correlate with poor survival of HCC patients. Thus, in this study, proteomics shed light on the molecular mechanism of LOXL4 during the development of HCC, and also provided new ideas for possible therapeutic intervention [ 62 ].…”