Project description:Disrupted iron metabolism is commonly observed in various types of cancer. However, the role of iron signaling in controlling the tumor microenvironment and its clinical relevance remain unclear. We found that intra-tumoral iron signals stabilized PD-L1 protein, dampening CD8+ T cell responses and promoting tumor evasion. Blocking iron uptake decreased PD-L1 expression and enhanced CD8+ T cell infiltration, leading to attenuated tumor growth. Mechanistically, iron preserved PD-L1 protein integrity by inhibiting its ubiquitination. Iron-induced lipid peroxidation in tumors promoted the generation of 4-Hydroxynonenal (4-HNE), which subsequently adducted to the PD-L1 cytoplasmic domain for its carbonylation. 4-HNE-mediated carbonylation outcompeted PD-L1 ubiquitination, resulting in PD-L1 protein stabilization. Finally, we introduced a designed peptide in tumor cells to diminish PD-L1 carbonylation by competing for 4-HNE availability. This led to decreased PD-L1 expression and enhanced CD8+ T cell immunity, hindering tumor growth. Importantly, such peptide therapy showed effective outcomes in anti-PD-L1 non-responding tumors. Thus, our findings reveal alternative strategies for overcoming PD-L1-mediated immune evasion in cancer.
Project description:Microarray analysis of liver tissue from WT SIRT6 and conditional knockout of SIRT6 using albumin-Cre (SIRT6Co/Co ;Alb-Cre) at 2 and 8 months of age RNA was extracted from mouse liver tissue at 2 and 8 months of age. RNA from three pairs of WT SIRT6 and SIRT6Co/Co ;Alb-Cre mice was combined and hybridized to Affymetrix mouse gene 1.0 ST arrays.
Project description:Microarray analysis of liver tissue from WT SIRT6 and conditional knockout of SIRT6 using albumin-Cre (SIRT6Co/Co ;Alb-Cre) at 2 and 8 months of age
Project description:Expression array analysis of mice livers with conditional deletion of autophagy related protein 7 (Atg7). Whole RNA from mice livers of 2 month old control (Atg7 FF), Olig1-CRE:Atg7 FF (conditional deletion in hepatocytes) and Alb-CRE:Atg7 FF (conditional deletion in hepatocytes/cholangiocytes) were analyzed. The results provide insight into the gene expression profile and role of autophagy in hepatocytes or hepatocytes/cholangiocytes in hepatic growth regulation and hepatocarcinogenesis.
Project description:Utilizing M. musculus as a model of mitochondrial dysfunction provides insight into cellular adaptations which occur as a consequence of genetic alterations causative of human disease. We characterized genome-wide expression profiles of liver-conditional knockout mice for Pdss2 compared with loxP controls. Our goal was to detect concordant changes among clusters of genes that comprise defined metabolic pathways utilizing gene set enrichment analysis. Experiment Overall Design: Liver from three biological replicates each of wildtype and coenzyme Q biosynthetic mutant M. musculus were used as sources of total RNA for hybridization to Affymetrix whole-genome microarrays. Comparison of the data was intended to reveal metabolic pathway alterations downstream of the mutation.
Project description:In order to further discover the resistance mechanism of Rack1F/F;Alb-cre mice to LPS/ GalN-induced fulfulant hepatitis, we used genome-wide microarray expression profiling as a discovery platform to identify potential genes associated with resistance to LPS/ GalN-induced in Rack1F/F;Alb-cre mice. Fulminant hepatitis was induced by LPS/GalN in Rack1F/F;Alb-cre mice and Rack1F/F mice for 0, 1,3 and 6 hours, respectively.
Project description:Utilizing M. musculus as a model of mitochondrial dysfunction provides insight into cellular adaptations which occur as a consequence of genetic alterations causative of human disease. We characterized genome-wide expression profiles of liver-conditional knockout mice for Pdss2 compared with loxP controls. Our goal was to detect concordant changes among clusters of genes that comprise defined metabolic pathways utilizing gene set enrichment analysis. Keywords: Wildtype vs mutant comparison as a method for studying contributors to disease processes.