The crosstalking immune cells network creates a collective function beyond the function of each cellular constituent during the progression of hepatocellular carcinoma

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.

Effective anti-tumor immune responses are orchestrated by immune cell partnership network that functions through tissue homeostatic pathways, not direct cytotoxicity

“…We have previously reported that collective function of the hepatic structural cells or immune cells is determined by dominant-subdominant interactions within the cellular networks 11 – 13 . Here, we sought to determine molecular pathways that dominate cell-cell interactions during the progression of NAFLD.…”

“…Under the influence of toxins including a chronic consumption of high fat and high sugar WD, the liver is subjected to a range of metabolic stresses and inflammatory signals that can initiate early carcinogenic processes 53 , which remain dormant before the formation of HCC. We have previously reported the presence of cancer cell dormancy in the FVBN202 transgenic mouse model of spontaneous breast cancer 20 as well as the DIAMOND model of NAFLD progression to HCC 11 . Here, we took multicellular networks immunology approach to study how immune cells interact within complex cellular networks to coordinate hepatic immune responses.…”

“…Taking a systems immunology approach, we have previously demonstrated that the immunological patterns reflecting collective immune functions during health and disease, can be understood through detection of dominant-subdominant interactions network among hepatic immune cells as well as nonimmune cells [11][12][13] . Such dominant-subdominant interactions have been reported in different settings as "cell competition" or "cellular fitness" in which the winner cells survive and eliminate the loser cells 14,15 .…”

“…We have previously reported that collective function of the hepatic structural cells or immune cells is determined by dominant-subdominant interactions within the cellular networks [11][12][13] .…”

“…Recent advancements in big data and computational algorithms have enabled the detection of cellular interactions as distinct networks, providing deeper insights into disease mechanisms. By adopting a systems immunology approach for understanding the progression of NAFLD to HCC, it has been demonstrated that dominant-subdominant relationships among hepatic immune cells shape immunological patterns from which collective functions emerge, distinct from the individual roles of each immune cell type [11][12][13] . These dominant-subdominant interactions are analogous to "cell competition" or "cellular fitness," where winner cells survive and eliminate loser cells 14,15 .…”