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

Autor:	Koelsch N; Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA., Mirshahi F; Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA.; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, VA 23298., Aqbi HF; College of Science, Mustansiriyah University, Baghdad, P.O. Box 14022, Iraq., Seneshaw M; Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA.; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, VA 23298., Idowu MO; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA.; VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA., Olex AL; VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA.; C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University School of Medicine., Sanyal AJ; Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA.; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, VA 23298.; VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA., Manjili MH; Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.; VCU Massey Comprehensive Cancer Center, Richmond, VA 23298, USA.; VCU Institute of Molecular Medicine, Richmond VA 23298.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI:	10.1101/2024.06.12.598563
Abstrakt:	The liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms. Competing Interests: Authors’ Disclosures A.J.S. and F.M. hold a patent on the DIAMOND mouse model, PCT/US2016/056506. All other authors do not have any competing interest.
Databáze:	MEDLINE
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