Dual Modifications of alpha-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 Carreno; Matthew J Guberman-Pfeffer; Pooja Arora; Yongqing Tang; Hui-Fern Koay; Dale I Godfrey; Santosh Keshipeddy; Stewart K Richardson; Srinivasan Sundararaj; Jae Ho Lo; Xiangshu Wen; Jose A Gascon; Weiming Yuan; Jamie Rossjohn; Jerome Le Nours; Steven A Porcelli; Amy R Howell

Journal article

Dual Modifications of alpha-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 Carreno, Matthew J Guberman-Pfeffer, Pooja Arora, Yongqing Tang, Hui-Fern Koay, Dale I Godfrey, Santosh Keshipeddy, Stewart K Richardson, Srinivasan Sundararaj, Jae Ho Lo, Xiangshu Wen, Jose A Gascon, Weiming Yuan, Jamie Rossjohn, Jerome Le Nours, Steven A Porcelli, Amy R Howell

CELL CHEMICAL BIOLOGY | CELL PRESS | Published : 2018

DOI: 10.1016/j.chembiol.2018.02.009

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 h..

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University of Melbourne Researchers

Dale Godfrey Author Microbiology and Immunology

Fern Koay Author Microbiology and Immunology

Jamie Rossjohn Author Microbiology and Immunology

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Grants

Awarded by NIH

Awarded by NSF Fellowship

Awarded by FONDECYT grant

Awarded by Australian Research Council (ARC) Future fellowship

Awarded by NCI grant

Awarded by Cancer Council Victoria

Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by Australian Research Council (ARC)

Awarded by Worldwide Cancer Research

Awarded by NHMRC

Awarded by Australian Research Council

Funding Acknowledgements

This work was supported by NIH grants U01 GM111849 (A.R.H., S.A.P., J.A.G., and W.Y.), R01 GM087136 (A.R.H.), RO1 AI45889 (S.A.P.), and R01 AI 091987 (W.Y.). M.G.-P. is supported by NSF Fellowship DGE-1247393. L.J.C. is supported by FONDECYT grant 1160336. J.L.N. is supported by an Australian Research Council (ARC) Future fellowship (FT160100074). Flow cytometry resources were supported in part by NCI grant CA13330 (Albert Einstein College of Medicine Cancer Center). This work was also supported by a program grant from the Cancer Council Victoria APP1042866, National Health and Medical Research Council of Australia (NHMRC) (1013667), the Australian Research Council (ARC) (CE140100011 and LP140100920), and the Worldwide Cancer Research (16-1106). D.I.G. was supported by NHMRC Senior Principal Research Fellowships (1020770, 1117766).