Metabolic-associated steatohepatitis (MASH) and pancreatic inflammation are key complications of obesity-related metabolic syndrome. Elevated IL-6; a proinflammatory cytokine, contributes to liver steatosis and pancreatic β-islet cells dysfunction. This study explores pancreatic tissue-resident (tr)NK cells IL-6 receptor (IL-6R) in pancreatic injury in a murine MASH model.
MASH models were established using male Ob/Ob mice fed a high-fat diet (Ob/Ob HFD; 60.3% kcal from fat) for 4 weeks and using immunocompromised NOD-SCID IL2rγnull (NSG) mice fed with HFD for 16 weeks and i.v. injected with 10 × 106 pancreatic trNK and treated with IL-6R antagonizing antibody on week 12. Biochemical assays assessed serum ALT, AST, lipids, glucose, and insulin levels. Pancreatic injury was analyzed through mRNA expression of Reg1, Reg3, oxidative stress marker of tissue malondialdehyde (MDA) and β-islet cells' proliferation and apoptosis. Fibrotic markers of α-SMA, Collagen-I, and Fibronectin were assessed via RT-PCR and trNK cell activation (CD107a, NKp46, IFN-γ) were assessed by flow cytometry.
Ob/Ob HFD mice exhibited increased serum cholesterol, triglycerides, fasting blood glucose, and liver injury enzymes. Markers of pancreatic injury of Reg1/Reg3 and pancreatic MDA with β-islet cells apoptosis were significantly elevated compared to littermates' control. These results were accompanied by a decline in trNK counts and activations (P < 0.05). In an adoptive transfer model, NSG mice fed with HFD and transplanted with trNK cells from Ob/Ob HFD donors (expressing high IL-6) exhibited similar pancreatic injury markers, whereas those receiving trNK cells from Ob/Ob HFD mice pre-treated with an IL-6R antagonist showed marked reductions in Reg1/Reg3 (∼2-fold), MDA (∼1.77-fold), and β-islet cells apoptosis (∼2.2-fold). Moreover, phenotypic characterization of the NSG mice fed an HFD transplanted with IL-6R antagonizing antibody showed an increase in the NK cell activation marker CD107a (∼2.3-fold) and amelioration in pancreatic fibrotic profile of α-SMA mRNA expressions of 1.6 -fold when compared to its counterparts.
Our data highlights the importance of IL-6R modulation on trNK cells in remodeling pancreatic tissue after liver injury, emphasizing the liver-pancreas axis as a therapeutic target to prevent pancreatic damage, β-islet cells dysfunction and fibrosis and reduce the risk of diabetes and metabolic syndrome.
Copyright © 2025 Amer, Arra, Salhab, Kayed, Maali, Shweiki and Ghanim.

Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh /AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which induces trimethylation of lysine 27 on histone 3 (H3K27me3) and promotes genes repression. EZH2 is overexpressed in many cancers including pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2. Deletion of the EZH2 enhances de novo KRAS-driven neoplasia following pancreatic injury by preventing acinar cell regeneration, while increased EZH2 expression in PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 function in pre-and early neoplastic stages of PDAC. Using an inducible model to generate deletion of EZH2 only in adult acinar cells (EZH2 ΔSET ), we showed loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRAS G12D ), nor lead to increased PanIN formation in the presence of KRAS G12D in adult mice. However, loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a PDAC model, promoted widespread PDAC progression. Loss of EZH2 function also correlated to remodeling of the tumor microenvironment, which favors cancer cell progression. This study suggests expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumour microenvironment and acinar cell differentiation.

All-trans-retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8+ T cell depletion antagonized ATRA's anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA's anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice-a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4+ T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4+ more than CD8+ T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.
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