Project description:Despite the remarkable success of immunotherapy in many types of cancer, pancreatic cancer has yet to benefit. Innate immune cells are critical players in antitumor immunosurveillance. Recent studies have revealed that innate immune populations may possess a form of memory, termed trained immunity through transcriptomic, epigenetic, and metabolic reprograming. 1Here, we show that intraperitoneal administration of yeast-derived particulate β-glucan results in 90% of that dose trafficking to the pancreas. This trafficking leads to a robust influx of newly characterized innate immune cells with an inflammatory monocyte/macrophage phenotype into the pancreas in a CCR2 dependent manner. These cells also exhibit a trained immunity phenotype upon exposure to tumor-derived factors and show enhanced phagocytosis and ROS-mediated cytotoxicity against pancreatic tumors. In orthotopic models of pancreatic cancer, mice trained with β-glucan show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with anti-PD-L1 immunotherapy. Cumulatively, these findings highlight a novel trafficking mechanism of yeast-derived particulate β-glucan that incites a phenotype of trained immunity specifically in the pancreas that can be utilized as an innovative strategy to treat pancreatic cancer.
Project description:Bone-marrow macrophages polarized to M2 phenotype are immunosuppressive. Interestingly, treatment with whole-glucan particles converts M2 macrophages to M1 phenotype with an anti-tumor phenotype. In this study, the effect of WGP treatment for 6 hours on the gene expression of M2 macrophages was assessed.
Project description:beta-glucan induced glycolysis in HIF-1 depedent manner. We reported that beta-glucan injection in mice led to upregulated glycolysis. HIF-1a plays a major role in this process. Mice receives beta-glucan via ip for 4 days. Splenocytes were isolated for RNA sequencing.
Project description:beta-glucan induced glycolysis in HIF-1 depedent manner. We reported that beta-glucan injection in mice led to upregulated glycolysis. HIF-1a plays a major role in this process.
Project description:Induction of trained immunity by beta-glucan affects myeloid cells and their bone marrow progenitors. In particular, broad alterations in the transcriptome of trained myeloid cells have been demonstrated. In this study, we performed RNA sequencing in GMP from beta-glucan treated mice, as compared to control-treated mice, in order to investigate the impact of trained immunity on the transcriptomic profile of GMP.
Project description:Induction of trained immunity by beta-glucan affects myeloid cells and their bone marrow progenitors. In particular, broad epigenetic alterations in trained myeloid cells have been demonstrated. In this study, we performed single cell ATAC sequencing in GMP and neutrophils from beta-glucan treated mice, as compared to control-treated mice, in order to investigate the impact of trained immunity on the epigenetic profile of GMP and neutrophils.
Project description:Analysis of transcriptional profiles in mDC sorted from apheresed PBMC and stimulated for 6 hours with cyclic glucan or LPS. The hypothesis tested is that cyclic glucan induces maturation and T cell-activation transcripts in human mDC. Total RNA extracted from mDC sorted from apheresed PBMC and activated for 6 hours with cyclic glucan or LPS.
Project description:Murine MDSCs isolated from the spleens of Lewis lung carcinoma mice were treated with or without WGP, and then miRNA array was used to analyze the differentailly expressed miRNAs. Murine MDSCs were isolated from the spleens of Lewis lung carcinoma tumor-bearing mice, and the sorted MDSCs were stimulated with or without 100 µg/ml WGP for 24 h. Then, the total RNA was extracted to perform miRNA array to analyze the differentially expressed miRNAs in MDSCs treated with or without WGP
Project description:Fungal beta-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in beta-glucan source, structure and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse beta-glucans we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogramme metabolism and thereby drive trained immunity in human monocyte-derived macrophages in-vitro and mice bone-marrow in-vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone-marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive immune training. Thus, the investment of a cell in a trained response relies on specific recognition of beta-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.