Enhancing T cell responses and tumour immunity by vaccination with peptides conjugated to a weak NKT cell agonist

BJ Compton; KJ Farrand; CW Tang; TL Osmond; M Speir; A Authier-Hall; J Wang; PM Ferguson; STS Chan; RJ Anderson; TR Cooney; CM Hayman; GM Williams; MA Brimble; CR Brooks; LK Yong; LS Metelitsa; DM Zajonc; DI Godfrey; O Gasser; R Weinkove; GF Painter; IF Hermans

Journal article

Enhancing T cell responses and tumour immunity by vaccination with peptides conjugated to a weak NKT cell agonist

BJ Compton, KJ Farrand, CW Tang, TL Osmond, M Speir, A Authier-Hall, J Wang, PM Ferguson, STS Chan, RJ Anderson, TR Cooney, CM Hayman, GM Williams, MA Brimble, CR Brooks, LK Yong, LS Metelitsa, DM Zajonc, DI Godfrey, O Gasser Show all

Organic and Biomolecular Chemistry | ROYAL SOC CHEMISTRY | Published : 2019

DOI: 10.1039/c8ob02982b

Abstract

Activated NKT cells can stimulate antigen-presenting cells leading to enhanced peptide antigen-specific immunity. However, administration of potent NKT cell agonists like α-galactosylceramide (α-GalCer) can be associated with release of high levels of cytokines, and in some situations, hepatotoxicity. Here we show that it is possible to provoke sufficient NKT cell activity to stimulate strong antigen-specific T cell responses without these unwanted effects. This was achieved by chemically conjugating antigenic peptides to α-galactosylphytosphingosine (α-GalPhs), an NKT cell agonist with very weak activity based on structural characterisation and biological assays. Conjugation improved delive..

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University of Melbourne Researchers

Dale Godfrey Author

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Grants

Awarded by National Institutes of Health

Funding Acknowledgements

This work was funded with grants from the Health Research Council of New Zealand (grant 14/500), the New Zealand Ministry of Business Innovation and Employment (grant RTV1603), the Thompson Family Foundation, Genesis Oncology Trust (grant GOT-1548-RPG) and support from Avalia Immunotherapies. D. I. G. is funded by a National Health and Medical Research Council (NHMRC) program grant (1113293), an Australian Research Council Centre of Excellence grant (CE140100011) and an NHMRC Senior Principal Research Fellowship (1117766). The authors thank the Biomedical Research Unit of the Malaghan Institute for animal husbandry, and the NIH Tetramer Core Facility for provision of the CD1d monomers. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program was supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.