Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity. Issue 5 (17th May 2018) - Chennamadhavuni, Divya
Summary: Glycosylceramides that activate CD1d-restricted invariant natural killer T ( i NKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising i NKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human i NKT cell responses. Here, we show that strongly proinflammatory and anti-tumor i NKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human i NKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic i NKT cell activators in the design of immunotherapeutic agents. Graphical Abstract: Highlights: Sphinganine α-galactosylceramides strongly activate mouse but not human i NKT cells A modification of galactose is described that restores human i NKT cell responses The modified α-GalCer retains improved proinflammatory and anti-tumor properties Crystallography and molecular modeling provide mechanistic insight into bioactivity Abstract : Chennamadhavuni et al. synthesized an improved activating ligand for i NKT cells by combining carbohydrate and sphingoid base modifications in an α-galactosyl ceramide. Biological and structural studies provide insight into the mechanisms responsible for improved activity and suggest approaches for further optimization of ligand design.