Biophysical insights into cancer lipid immune presentation 3564

Abstract Description CD1 restricted T cells are a specialized subclass of T cells that are designed to recognize lipid antigens instead of traditional peptide or carbohydrate antigens. This part of the immune system involves lipid presentation by specialized MHC-like molecules called CD1 to subsets of T cells including iNKTs. Upon recognition of a foreign lipid, iNKTs mount a potent immune response that includes the release of multiple immunostimulatory cytokines. Recently, modified lipids that are exclusively expressed in cancer cells have been discovered. Interestingly, these lipid have been found to activate the immune system through the CD1 presentation and subsequent iNKT stimulation. Unfortunately, biophysical and structural insights underpinning the molecular interactions of cancer-specific lipid/CD1 assemblies and subsequent interaction with specific T cells is currently lacking. Here, we describe the synthesis of cancer lipids leukemia-specific mLPA and carcinoma specific α-FucCer. We also discuss the application of tryptophan fluorescence together with cutting-edge biophysical techniques nanoDSF and MST to probe the interaction between CD1 and cancer lipids for the first time. Finally, we provide the first atomic models of cancer lipid/CD1 assemblies using machine-learning based structure prediction software RoseTTAFold All-Atom. Together, our results provide the first biophysical and structural insights into cancer lipid antigen presentation by the CD1 immunoreceptor. Funding Sources Supported by the Shurl and Kay Curci Foundation Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)