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

The strength of the reductionist approach lies in a focused and precise analysis of individual components viewed in isolation yet missing the mutual interconnection and feedback loops between the various cellular components that create dynamically changing immune responses, as well as failure to understand the emergent properties of the immune response as a system operating at the level of the tumor microenvironment. In fact, it often misses the “forest for the trees”. Accordingly, there is an pressing need to balance reductionism with a systems immunology approach to obtain a comprehensive understanding of immune functions. In a recent article published in Scientific Reports, Drs. Manjili and Sanyal of VCU and VIMM along with colleagues Nicholas Koelsch, Faridoddin Mirshahi, Mulu Saneshaw, Hussein Aqbi, Michael O. Idowu and Amy Olex, have shown that the immunological pattern, rather than each immune cell alone, can better explain the immunobiology of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). They report that progressive NAFLD or NASH and HCC cannot be described solely by tumor immune tolerance or immune suppression, because these mechanisms focus on each cell component, which do not reflect the collective immune functions. In fact, focusing on each immune cell type, pro- or anti-inflammatory cells, would mask and miss important functional mechanisms and cellular dynamics, which can only be detected by the discovery of the hepatic immunological patterns that create collective functions.

Highlights of the study:

• Innate immune cells, M1 macrophages in particular, recruited into the liver are the major players orchestrating liver fibrosis and progression of HCC.
• Predicted collective immune function in the liver is beyond the function of its cellular constituents, which is absent or undetectable when each single cell type is analyzed separately.
• Each predicted collective immune function arises from a cross-talking network of immune cells dynamically entangled and interacting with one another and with the hepatic structural cells; it is similar to the behaviors of a flock of birds arising from the interactions between individual birds, rather than from the behavior of any single bird.
• Such predicted collective immune function can be understood by the discovery of dominant-subdominant patterns of immune cells interactions as super-patterns as well as inferior-patterns during tumor progression.

By taking a systems immunology approach, we detected multilayered immunological patterns, extending from super-patterns to inferior-patterns, and shifting from the super-patterns of dominant adaptive immunity (B and T cells) > innate immunity (macrophages and monocytes) to the dominant innate > adaptive immunity during the progression of HCC (Figure 1). The collective functions, which were independent from and beyond the function of its cellular constituents (innate or adaptive immune cells), missed key immune mechanisms associated with the progression of NAFLD and HCC when each immune cell type was analyzed separately.

The hepatic immune patterns that we discovered in the present study are limited to the methodology we used including SingleR containing reference database for annotating major cell types, and scSorter. Further analyses may be needed to achieve a comprehensive understanding of the hepatic immunological patterns.

Figure 1. Pattern assessment of the hepatic immune and non-immune cells: Multilayered immunological patterns during health and diseases, manifesting super-patterns and inferior patterns were quantitatively analyzed by focusing on the ratios/proportion of immune cells interacting with each other in a network.

* This work was supported by funding from NIH R01DK105961, Massey Cancer Center Muti-Investigator Award, grant number 2017-MIP-2, and 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, and from the VCU Cancer Mouse Models Core Shared Resource (CMMC) supported, in part, by funding from the NIH-NCI Cancer Center Support Grant P30 CA 016059.

Publication:

* Koelsch N, Mirshahi F, Aqbi HF, Saneshaw M, Idowu MO, Olex AL, Sanyal AJ, Manjili MH. The crosstalking immune cells network creates a collective function beyond the function of each cellular constituent during the progression of hepatocellular carcinoma. Sci Reports 13(1):12630, 2023 PMID: 37537225. PMCID: PMC10400568

About the Investigators: Nicholas Koelsch is a graduate student in the Manjili laboratory; Faridoddin Mirshahi is an Instructor in the Department of Internal Medicine, Hussein Aqbi was a graduate student in the Manjili laboratory, Mulu Saneshaw is a member of the Sanyal laboratory, Michael Idowu is a Professor of Pathology, Department of Pathology, Amy Olex is a bioinformatic specialist at C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Arun Sanyal is a Professor of Medicine in the Department of Internal Medicine, and Masoud H Manjili is a Professor of Immunology in the Department of Microbiology and Immunology, VCU School of Medicine, VCU Massey Cancer center and a member of VIMM.