Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer Macrophages

BACKGROUND & AIMS: Complex communications between hepatocytes and Kupffer cells (KCs) are known to drive or suppress hepatocarcinogenesis, with controversial data in the literature. In previous experiments that aimed to decipher he-patocyte/KC interactions, we unexpectedly unveiled a tumor-suppressing effect of polyinosinic-polycytidylic acid, a widely used inducer of MX dynamin like GTPase 1 (Mx1)-cre expres-sion, which questioned a theory of interleukin 1a/6 cytokine circuit in hepatocyte/KC communication. The goal of this study was to clarify the controversy and decipher unique functions of KCs and non-KC macrophages in liver tumorigenesis.METHODS: We used the C-type lectin domain family 4 member F (Clec4f)-cre system to delete Src-homology 2 domain-containing tyrosine phosphatase 2 (Shp2)/protein tyrosine phosphatase nonreceptor 11 (Ptpn11) in KCs, and a combination of Clec4f-cre and adeno-associated virus-cre to delete Shp2 in KCs and he-patocytes to investigate the effects on hepatocellular carcinoma development and immune cell compositions/activities.RESULTS: Ablating Shp2 in KCs generated a tumor-promoting niche, which was exacerbated further by concurrent removal of Shp2 in both KCs and hepatocytes. Shp2 deficiency induced KC apoptosis and decreased its numbers, which induced compen-satory recruitment of bone marrow-derived monocytes into liver. These newly recruited monocytes differentiated into non-KC macrophages with tumor-associated macrophage function, lead-ing to aggravated tumor progression through down-regulation of CD8 T cells. Tumor-associated macrophage blockade by anti-chemokine (C-C motif) ligand 2 (CCL2) antibody inhibited hepatocellular carcinoma progression, while depletion of all macrophages had a tumor-promoting effect by increasing myeloid-derived suppressor cells (M-MDSCs) and decreasing CD8 T cells. CONCLUSIONS: Shp2 loss in KCs or hepatocytes generated a protumorigenic microenvironment, which was exacerbated by its removal in both cell types. These results show the complexity of intercellular signaling events in liver tumori-genesis and raises caution on the use of specific Shp2 inhibitor in liver cancer therapy. Transcript profiling: RNA sequencing data are available at Gene Expression Omnibus (GSE222594). (Cell Mol Gastroenterol Hepatol 2023;15:1351-1369; https:// doi.org/10.1016/j.jcmgh.2023.02.011)

Automated summary

The study aimed to clarify the interactions between hepatocytes and Kupffer cells and investigate the unique functions of Kupffer cells and non-Kupffer macrophages in liver tumorigenesis. It found that deleting the Shp2 gene in Kupffer cells generated a tumor-promoting environment, which was exacerbated by concurrent removal of Shp2 in hepatocytes.