Trim21 deficiency in mice increases HCC carcinogenesis in a NASH context and is associated with immune checkpoint upregulation

Abstract

The global pandemic of metabolic diseases has increased the incidence of hepatocellular carcinoma (HCC) in the context of non-alcoholic steatohepatitis (NASH). The downregulation of the E3 ubiquitin ligase TRIM21 has been linked to poor prognosis in different cancers including HCC. In order to investigate the role of TRIM21 in liver cancer progression on NASH, Trim21^+/+ and Trim21^-/- male mice were injected with streptozotocin at the neonatal stage. The hypoinsulinemic mice were then fed with a high-fat high-cholesterol diet (HFHCD) for 4, 8 or 12 weeks. All mice developed NASH which systematically resulted in HCC progression. Interestingly, compared to the Trim21^+/+ control mice, liver damage was worsened in Trim21^-/- mice, with more HCC nodules found after 12 weeks on HFHCD. Immune population analysis in the spleen and liver revealed a higher proportion of CD4⁺PD-1⁺ and CD8⁺PD-1⁺ T cells in Trim21^-/- mice. The liver and HCC tumors of Trim21^-/- mice also exhibited an increase in the number of PD-L1⁺ and CD68⁺ PD-L1⁺ cells. Thus, TRIM21 limits the emergence of HCC nodules in mice with NASH by potentially restricting the expression of PD-1 in lymphocytes and PD-L1 in tumors.

Keywords: HCC; NASH; PD‐1; PD‐L1; TRIM21.