The objective of this R21 proposal is to demonstrate the concept that engineered nanostructures of ligands provide a highly effective platform for the investigation and programming of the immune response of dendritic cells (DCs). Taking advantage of exquisite spatial precision, enabled by a nanofabrication method known as atomic force microscopy (AFM)-based nanografting which was invented in the PI's laboratory, chosen ligands such as lipopolysaccharide(LPS) molecules, are accurately positioned on supports with designed spatial arrangement and numbers for recognition by toll-like receptors (TLRs) such as TLR-4 on DCs'membrane surface. By varying the number and spatial arrangement of ligands in the nanostructures, in conjunction with antigen pulsing, desired immune responses could be attained and harnessed for anti-tumor therapy. This approach is based upon the hypothesis - validated by our preliminary studies and current knowledge of DC immunology - that clustering of ligand-TLR complexes dictates subsequent immune signaling cascades, such as maturation and antigen presentation. The concept differs intrinsically from currently in vitro approaches due to its molecular level control of the number and the distributions of ligand-TLR complexes. As such, DCs with desired immune profiles could be engineered and generated for subsequent translational research and in vivo applications including tissue engineering, and DC vaccine development for anti-cancer therapy, and T-cell anti-tumor therapy.
Dendritic cells play a critical role in the immune system to stimulate T-cells for anti-tumor activities. Therefore, dendritic cell-based therapy has the potential to stimulate one's own immune system to kill tumor cells. However, most if not all, approaches remain ineffective clinically due to insufficient activation and/or inadequate antigen presentation capabilities of dendritic cells. The nanotechnology approach introduced in this proposal provides a molecular level-based approach to enable engineering dendritic cells'maturity and antigen presentation capability to attain required immunity.
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