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Publication Abstract from PubMed

Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of alpha-galactosylceramide as promising iNKT 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 iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of alpha-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 iNKT 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 iNKT cell activators in the design of immunotherapeutic agents.

Dual Modifications of alpha-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity.,Chennamadhavuni D, Saavedra-Avila NA, Carreno LJ, Guberman-Pfeffer MJ, Arora P, Yongqing T, Koay HF, Godfrey DI, Keshipeddy S, Richardson SK, Sundararaj S, Lo JH, Wen X, Gascon JA, Yuan W, Rossjohn J, Le Nours J, Porcelli SA, Howell AR Cell Chem Biol. 2018 Mar 9. pii: S2451-9456(18)30073-4. doi:, 10.1016/j.chembiol.2018.02.009. PMID:29576533^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.