A shift in the hepatic immunological pattern from predominant adaptive immunity to innate immunity compromises tissue-specific immunity and leads to HCC

Abstract The incidence of hepatocellular carcinoma (HCC) associated with non-alcoholic fatty liver disease (NAFLD) is growing because of the global consumption of high fat, high sugar or Western diet (WD). Current data suggests a correlation between the hepatic inflammation and progression of NAFLD to HCC. However, contradictory reports on the identification of specific inflammatory cells or cytokines hinder further progress in the field. Such controversial reports are due to highly reductionist approaches and getting lost in the details. By using flow cytometry, we have demonstrated that the hepatic immunological patterns were associated with the progression or inhibition of HCC, which can be discovered through the detection of the proportion of immune cell types functioning as a network. However, flow cytometry utilizes a limited number of markers hindering a comprehensive detection of the patterns. Here, we perform scRNAseq of the liver collected from the mouse model of NAFLD (DIAMOND) being on a WD prior to or after the development of HCC, as well as control mice being on a chow diet (CD). We demonstrate that a WD alters the hepatic immunological pattern by dominating innate immunity, M1 macrophages, over adaptive immunity, B and T cells, associated with the activation of the hepatic fibroblasts. Each immunological pattern created a distinct collective function beyond the function of its cellular constituents. Also, shifts in the immunological pattern compromised the hepatic immune system, transforming its anti-tumor function to carcinogenesis-promoting process. Our data suggest that the discovery and modulation of the hepatic immunological pattern could offer a comprehensive understanding of and curative treatment for NAFLD and HCC. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense.This work was also supported, in part, by CTSA award No. UL1TR002649 from the National Center for Advancing Translational Sciences.