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Abstract 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 focusing on detailed specific cell types and missing the collective function of the hepatic immune system. 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. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC.

The tumor microenvironment (TME) is a complex and dynamic ecosystem that includes a variety of immune cells mutually interacting with tumor cells, structural/stromal cells, and each other. The immune cells in the TME can have dual functions as pro-tumorigenic and anti-tumorigenic. To understand such paradoxical functions, the reductionistic approach classifies the immune cells into pro- and anti-tumor cells and suggests the therapeutic blockade of the pro-tumor and induction of the anti-tumor immune cells. This strategy has proven to be partially effective in prolonging patients’ survival only in a fraction of patients without offering a cancer cure. Recent advances in multi-omics allow taking systems immunology approach. This essay discusses how a systems immunology approach could revolutionize our understanding of the TME by suggesting that internetwork interactions of the immune cell types create distinct collective functions independent of the function of each cellular constituent. Such collective function can be understood by the discovery of the immunological patterns in the TME and may be modulated as a therapeutic means for immunotherapy of cancer.

Predominant inflammatory immunological patterns as well as the depletion of CD4+ T cells during nonalcoholic fatty liver disease (NAFLD) are reported to be associated with the progression of hepatocellular carcinoma (HCC). Here, we report that an LRP-1 agonistic peptide, SP16, when administered during advanced NAFLD progression, restored the depleted CD4+ T cell population but did not significantly affect the inflammatory immunological pattern. This data suggests that restoration of CD4+ T cells without modulation of the hepatic immunological pattern is not sufficient to prevent HCC. However, SP16 administered early during NAFLD progression modulated the inflammatory profile. Future studies will determine if regulation of the inflammatory immune response by SP16 early in NAFLD progression will prevent HCC.