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

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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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 NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


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).