Yvette van Kooyk More on research
Dendritic Cell Immunobiology
Dendritic cells are antigen-presenting cells well known for their function to stimulate or inhibit immune responses. In our group we focus on innate receptors, such as Toll-like receptors and C-type lectins to modify immune responses. Because we study C-type lectin receptors known to recognise specific carbohydrate profiles on pathogens and on self glycoproteins our research groups aims to understand glycan mediated responses. Using biochemical and immunological readout systems we unravel new molecular pathways crucial in directing dendritic cells towards immunity or tolerance as dendritic cell communications such as cell adhesion, migration and signalling. Also our understanding in regulatory responses involved in glycosylation changes during onco-development is studied. Our fundamental insights in DC biology will provide tools for modulating dendritic cell mediated immune responses aimed to be translational applied in cancer and autoimmune diseases and biomarker development. The research is clustered in three focus lines.
1. Identification of new molecular interactions in DC biology
We have identified a multitude of glycan- C-type lectins interactions that contribute to the innate recognition of dendritic cells and it further consequences on the adaptive immunity. Not only antigen presentation and cell-adhesion is mediated by glycan lectin interactions but also signalling and Th cell differentiation. Our interest is focused on understanding how DC regulatory signalling mechanisms are activated upon recognition of well identified glycan structures (immune activating or suppressive). These fundamental details will unveil new mechanisms that are key in DC programming and may for new leads in translational applications for cancer and autoimmune diseases.
2. Inhibitory signalling through glycans within the tumor-microenvironment
We have identified several glycan-lectin interactions that have an immune inhibitory function. Some of these glycan modification are increased on tumor cells.
Current studies are focused on unraveling how these glycans alter DC function and the innate immune repertoire. On the other hand we use these inhibitory glycans to modify antigens towards an immuneinhibitory mode to dampen auto-immune diseases such as Multiple Sclerosis.
3. DC-antigen recognition and presentation, novel vaccination strategies
Targeting of antigen to C-type lectins on DC/LC has been shown to improve antigen presentation to induce antigen specific CD4 and CD8 T cells. We molecularly define the internalisation of antigen that leads to superior cross-presentation of DC/LC that enhance T cell responses. We design new vaccination strategies that include glycosylated antigen formulation as peptide networks or liposomes as nanomedicine that will induce potent anti-tumor CD8 and CD4 T cell responses in in-situ human skin model systems and in-vivo models of melanoma, glioblastoma and pancreatic cancer. Key in our studies in the design of tumor vaccines is to understand molecular events necessary to optimally modulate skin DC/LC for the induction of tumor immunity. Multi-parameter flow analysis is key in the identification of functional quality and duration of tumor specific immunity as well as the analysis of the tumor microenvironment. Our DC targeted vaccines are combined by combinational therapy using checkpoint inhibition by monoclonal antibodies, or interference of the tumor glycosylation.