Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma.

Leukocyte cell-derived chemotaxin-2 (LECT2) was originally identified as a hepatocyte-secreted chemokine-like factor and a positive target of ß-catenin signaling. Here, we dissected out the mechanisms by which LECT2 modulates hepatocellular carcinoma (HCC) development using both HCC mouse models and human HCC samples. We have demonstrated that LECT2 exhibits dual abilities as it has profound repercussions on the tumor phenotype itself and the immune microenvironment. Its absence confers Ctnnb-1-mutated tumor hepatocytes a stronger ability to undergo epithelial to mesenchymal transition and fosters the accumulation of pejorative inflammatory monocytes harboring immunosuppressive properties and strong tumor-promoting potential. Consistent with our HCC mouse model, a low level of LECT2 in human HCC is strongly associated with high tumor grade and the presence of inflammatory infiltrates, emphasizing the clinical value of LECT2 in human liver tumorigenesis. Conclusion: Our findings have demonstrated that LECT2 is a key player in liver tumorigenesis because its absence reshapes the tumor microenvironment and the tumor phenotype, revealing LECT2 as a promising immunotherapeutic option for HCC.

Oncogenic ß-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding ß-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of ß-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic ß-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by ß-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver ß-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic ß-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in ß-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro- and antiinflammatory mediators, ß-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most ß-catenin-activated HCCs are of better prognosis.

Regression of established liver tumor induced by monoepitopic peptide-based immunotherapy.

Most types of cancer are difficult to eradicate, and some, like hepatocellular carcinoma, are almost always fatal. Among various interventions to improve the survival of patients with cancer, immunotherapy seems to hold some promises. However, it requires relevant animal models for preclinical development. In this study we report a new and relevant experimental model where liver tumors grow inside a nontumoral parenchyma of adult mice. This model is based on the intrasplenic injection in syngeneic recipient mice of hepatocytes from transgenic mice expressing SV40 large T oncogene specifically in the liver. Using this model where no apparent spontaneous cellular immune response was observed, immunization using a single injection of monoepitopic SV40 T Ag short peptide was sufficient to provoke liver tumor destruction, leading rapidly to complete remission. Tumor regression was associated with the induction of a long-lasting CD8+ T cell response, observed not only in the spleen but also, more importantly, in the tumoral liver. These results show the efficacy of peptide immunotherapy in the treatment of liver cancer.