Project description:Transcriptional profiles of four different myeloid antigen presenting cell (APC) subsets (BDCA-1+ circulating myeloid dendritic cells, CD14+ monocytes, and in vitro generated immature and mature monocyte-derived dendritic cells) were used for comprehensive transcriptome analysis. Based on the gene expression profiling data, a quantitative relationship between myeloid APC in functionally related gene spaces was established. Keywords = myeloid antigen presenting cells Keywords = dendritic cell subsets Keywords: repeat sample
Project description:Dr. van Kooyk's laboratory is exploring the function of antigen presenting cells, such as dendritic cells (DC), that regulate viral-antigen recognition, DC trafficking and T cell binding--all processes that initiate immunity or tolerance. Essential in this is the recognition of ligands by C-type lectins and the functional consequences of differential terminal glycosylation that may regulate DC function. In this study, the gene expression profile of glycosylation-related genes is examined in relation to the maturation of human antigen-presenting cells. Two pooled RNA samples, one each from immature and mature human monocyte-derived dendritic cells, were prepared and sent to Microarray Core (E). The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays.
Project description:Dendritic cell (DC) vaccines have been proposed as cancer immunotherapies due to their role as crucial antigen-presenting cells that regulate T cell functions. Despite considerable efforts to optimize ex vivo priming of DCs, DC vaccines have rarely been successful, suggesting the presence of unknown inhibitory factors. Here, we examined DC differentiation dynamics and discovered that ALDH1a2-produced retinoic acid (RA) acts as a bottleneck factor, initiating negative feedback to inhibit DC maturation. Removing this inhibition through either genetic knockout or pharmacological blockade using KyA33, an ALDH1a2 inhibitor we developed, significantly enhances DC maturation, phagocytosis, antigen presentation, and T cell activation, in part by downregulating glucose metabolism. KyA33 demonstrates favorable drug-like properties, including low toxicity, high membrane permeability, and low cell efflux rate. Its non-covalent binding to ALDH1A2 was also validated through X-ray crystallography. Importantly, application of KyA33 generates more robust DCs vaccines, promoting anti-tumor immunity through enhancing antigen-specific T cell responses. Our investigation highlights the intricate interplay between retinoid signaling, dendritic cell maturation, and immune metabolism, offering promising avenues for enhancing cancer immunotherapies.
Project description:Dr. van Kooyk's laboratory is exploring the function of antigen presenting cells, such as dendritic cells (DC), that regulate viral-antigen recognition, DC trafficking and T cell binding--all processes that initiate immunity or tolerance. Essential in this is the recognition of ligands by C-type lectins and the functional consequences of differential terminal glycosylation that may regulate DC function.
Project description:Myeloid immune cells play a major role in establishing a suitable microenvironment for metastatic tumor cells. Dysregulated myeloid cells suppress antigen-presentation pathways and effector T cell responses at distal organs, and reprogramming these cells may enhance anti-tumor cytotoxicity. Targeting myeloid cells with poly(lactide-co-glycolide) nanoparticles, which possess intrinsic immunomodulatory properties, can promote monocyte maturation to inhibit metastasis. Intravenously delivered nanoparticles made with polyvinyl alcohol, but not other surfactants, reduce the accumulation of neutrophils at the metastatic niche and induce the differentiation of monocytes into antigen-presenting monocyte-derived dendritic cells. The internalization of nanoparticles was linked to the upregulation of gene expression programs in monocyte-derived dendritic cells associated with antigen presentation and T cell stimulation, and ligand-receptor network modeling supports increased activation of Th1 cells by these monocyte-derived dendritic cells. Nanoparticle administration increased the proportion of CD4 cells with Th1 and Th17 phenotypes and did not inhibit metastasis in mice where monocytes or T cells were depleted, indicating that interactions between monocyte-derived dendritic cells and T cells are essential to the mechanism of action. Collectively, our findings demonstrate that nanoparticles can reprogram circulating monocytes into monocyte-derived dendritic cells to modulate the metastatic niche and enhance antigen presentation to stimulate intrinsic T cell responses.
Project description:To characterize thymic APCs in an unbiased manner, we generated a scRNA-seq atlas of thymic antigen presenting cells (APCs) isolated from thymic rosettes, cellular complexes of physically interacting thymocytes and APCs. Around 8,000 APCs were captured, mostly haematopoietic in origin, consisting of B cell, dendritic cell and macrophage lineages.
Project description:This trial is to compare the efficacy and safety of modified FOLFOX6 [mFOLFOX6, a specific chemotherapy regimen of Oxaliplatin ,5-Fluorouracil and Leucovorin] chemotherapy plus Antigen Pulsed Dendritic Cells (APDC,a kind of autologous tumor lysates pulsed human dendritic cells vaccine) with modified chemotherapy alone in patients with metastatic colorectal cancer.