BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe, chronic liver inflammation often with fibrosis, that can progress to hepatocellular carcinoma (HCC). How some patients evolve from benign steatosis to NASH and subsequently to HCC remain elusive. Triggering Receptor Expressed on Myeloid cells (TREM) are cell surface glycoproteins that participate in innate immune response. TREMs lack signaling capabilities of their own and associate with TYRO Protein Tyrosine Kinase Binding Protein (TyroBP), that signals through immuno receptor tyrosine-based activation motif (ITAM). We and others have recently found that TREM2 is upregulated in NASH and fibrotic scar associated macrophages. However, it is not clear whether TREM2 expression is harmful or protective during NASH-HCC. METHODS: We used three different models of NASH-Fibrosis-HCC: (1) Foz/Foz mice fed with Western Diet (WD) closely mimics human NASH and NASH-HCC (Ganguly et. al. CMGH 2021). Foz/Foz and Trem2 -/-: :Foz/Foz were put on Western Diet (WD) (2) WT and Trem2 -/- mice were fed WD and 30% Fructose in drinking water. (3) WT and Trem2 -/- mice were administered CCl4. TREM2 and TyroBP expression was analyzed in human NASH livers. Single cell RNAseq was used to identify the cellular compartments where TREM2 and TyroBP are primarily expressed and elucidate the gene signatures associated with TREM2 expression. Mouse hepatic cytokine profiling was done using multiplex cytokine analyses (Luminex). RESULTS: TREM2 is primarily expressed in macrophages, both in the liver resident Kupffer cells and recruited macrophages. TyroBP is however expressed in multiple hepatic cell types. TREM2 induction is an early event during NASH. TREM2 expression increases with the severity of NASH-fibrosis and remains high during the HCC stage. Analyses of human NASH datasets confirms that TREM2 expression is induced during human NASH. We also found that TREM2 is upregulated in DEN (Diethylnitrosamine) induced tumors, and Tak1ΔHep mice tumors. Absence of TREM2 accelerated diet induced NASH, fibrosis, and HCC development. Fibrosis was also exacerbated in the Trem2 -/- mice in the CCl4 model. Several pro-inflammatory cytokines such as KC, MCP1, MIP2, IL1a, IL1b were elevated in the livers of Trem2 -/- mice during NASH-HCC. CONCLUSIONS: Taken together, our data indicates that absence of TREM2 accelerates both NASH and NASH associated HCC development.
PCL22-187 Table 1: Clinicopathologic Features of Primary Extremity STS Patients from the US Sarcoma Collaborative Validation Cohort and the Sarculator Development Cohort10
PCL22-187 Table 2: Clinicopathologic Features of Primary Extremity STS Patients from the US Sarcoma Collaborative and Memorial Sloan Kettering Cancer Center (MSKCC) Validation Cohorts11
PCL22-187 Table 3: Univariate and Multivariable Cox Regression for Overall Survival in Extremity STS Patients
PCL22-187 Table 4: Univariate and Multivariable Cox Regression for Time to Distant Metastases in Extremity STS Patients
PCL22-187 Table 5: Univariate and Multivariable Cox Regression for Disease-Specific Survival in Extremity STS Patients