Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity

Divya Chennamadhavuni, Noemi Alejandra Saavedra-Avila, Leandro J. Carreño, Matthew J. Guberman-Pfeffer, Pooja Arora, Tang Yongqing, Hui Fern Koay, Dale I. Godfrey, Santosh Keshipeddy, Stewart K. Richardson, Srinivasan Sundararaj, Jae Ho Lo, Xiangshu Wen, José A. Gascón, Weiming Yuan, Jamie Rossjohn, Jérôme Le Nours, Steven A. Porcelli, Amy R. Howell

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 α-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 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 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. Chennamadhavuni et al. synthesized an improved activating ligand for iNKT 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.

Original languageEnglish (US)
Pages (from-to)571-584.e8
JournalCell Chemical Biology
Volume25
Issue number5
DOIs
StatePublished - May 17 2018

Keywords

  • CD1d
  • KRN7000
  • cancer immunotherapy
  • galactosylceramide
  • iNKT cells
  • tumor immunity
  • α-GalCer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Chennamadhavuni, D., Saavedra-Avila, N. A., Carreño, L. J., Guberman-Pfeffer, M. J., Arora, P., Yongqing, T., Koay, H. F., Godfrey, D. I., Keshipeddy, S., Richardson, S. K., Sundararaj, S., Lo, J. H., Wen, X., Gascón, J. A., Yuan, W., Rossjohn, J., Le Nours, J., Porcelli, S. A., & Howell, A. R. (2018). Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity. Cell Chemical Biology, 25(5), 571-584.e8. https://doi.org/10.1016/j.chembiol.2018.02.009