The hepatic immunological pattern shaped by dominant-subdominant cellular relationship creates a collective function beyond the function of each cellular constituent to orchestrate the progression of hepatocellular carcinoma

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of taking reductionist approaches and missing the collective function of the hepatic immune system by focusing on specific immune cell type. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Within different immune pattern, the same cytokines manifest different functional signaling pathways. These data suggest that discovery of the immune pattern not only explains dynamic changes in immune cells during the course of diseases but also offers immune modulatory approaches for the treatment of NAFLD and HCC. Overall design: Six DIAMOND mice (129A1/SvIm and C57BL/6J cross mice) were stratified into experimental groups receiving different diets at two months of age. Two mice (n=2) were included in the control group (fed a standard chow diet (CD) for 40 weeks), two were in the Pre-T group (prior to tumor development; fed a high-fat diet with sugar water for 40 weeks), and the last two in the Post-T group (after tumor development due to being on high-fat diet with sugar water for 48 weeks) to recapitulate the changes seen during the progression of non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC).