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

Benjamin J. Compton, Kathryn J. Farrand, Ching Wen Tang, Taryn L. Osmond, Mary Speir, Astrid Authier-Hall, Jing Wang, Peter M. Ferguson, Susanna T.S. Chan, Regan J. Anderson, Taylor R. Cooney, Colin M. Hayman, Geoffrey M. Williams, Margaret A. Brimble, Collin R. Brooks, Lin Kin Yong, Leonid S. Metelitsa, Dirk M. Zajonc, Dale I. Godfrey, Olivier GasserRobert Weinkove, Gavin F. Painter, Ian F. Hermans

Research output: Contribution to journalArticleResearchpeer-review

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 delivery to antigen-presenting cells in vivo, while use of a cathepsin-sensitive linker to release the α-GalPhs and peptide within the same cell promoted strong T cell activation and therapeutic anti-tumour responses in mice. The conjugates activated human NKT cells and enhanced human T cell responses to a viral peptide in vitro. Accordingly, we have demonstrated a means to safely exploit the immunostimulatory properties of NKT cells to enhance T cell activation for virus- and tumour-specific immunity.

Original languageEnglish
Pages (from-to)1225-1237
Number of pages13
JournalOrganic and Biomolecular Chemistry
Volume17
Issue number5
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Compton, B. J., Farrand, K. J., Tang, C. W., Osmond, T. L., Speir, M., Authier-Hall, A., Wang, J., Ferguson, P. M., Chan, S. T. S., Anderson, R. J., Cooney, T. R., Hayman, C. M., Williams, G. M., Brimble, M. A., Brooks, C. R., Yong, L. K., Metelitsa, L. S., Zajonc, D. M., Godfrey, D. I., ... Hermans, I. F. (2019). Enhancing T cell responses and tumour immunity by vaccination with peptides conjugated to a weak NKT cell agonist. Organic and Biomolecular Chemistry, 17(5), 1225-1237. https://doi.org/10.1039/c8ob02982b