MD, PhD, FMedSci
Professor of Immunology
- Head of Division of Investigative Medicine
- Director of MRC Human Immunology Unit
Vaccination, cancer immunology and NKT cell function
The principal aim of the Research in my laboratory is to gain a better understanding of the mechanisms that control the cell-cell interplay required for optimal expansion and activation of tumour-specific T cell populations and to apply this knowledge to the development of better treatment strategies in cancer patients. Research in my laboratory is divided into three complementary areas:
- Analysis of tumour-specific immune responses in melanoma patients and the role of the tumour micro-environment in hampering tumour-specific immune responses;
- Structural, kinetic and functional analyses of invariant NKT (iNKT) cell activation;
- Clinical trial vaccine programme in melanoma patients.
1) Analysis of the Tumour-Specific Immune Response
By using HLA class I tetramers we have gained an understanding of the tumour-specific immune response, and have been able to show that in some patients with metastatic melanoma there are expanded populations of tumour-specific cytotoxic T lymphocytes.
We have recently started a research programme focused on the role of the tumour micro-environment in suppressing tumour-specific immune responses. The results of our studies have demonstrated the ability of invariant NKT cells to modulate the phenotype of Il-10 secreting myeloid cells in a large proportion of melanoma patients. These cells suppress proliferation and activity of tumour-specific T cell responses (De Santo et al. 2010). More recently, we have extended these results by demonstrating: i) the ability of tumours to up-regulate a novel tryptophan specific transporter to survive in a low nutrients microenvironment (Silk et al. 2011); ii) secretion of arginase II by a large proportion of AML blasts, which significantly hampers T cell and haematopoietic stem cell proliferation (Mussai et al., Blood 2013); In addition, we have initiated a programme to study how tissue stroma can modulate the expression of tissue homing receptors. It is known that the production of retinoic acid (RA) by dendritic cells (DCs) is critical for driving the development of gut-tropic immune responses; however, the factors that regulate RA synthesis by DCs remain poorly defined. We have recently demonstrated the role of prostaglandin E2 (PGE2) in blocking the expression of the retinal dehydrogenases (RALDH), the enzymes responsible for converting vitamin A into RA, and abrogating their ability to induce CCR9 expression upon T cell priming (Stock et al. 2011).
2) Structural, Kinetic and Functional Analyses of iNKT Cell Activation
We and others have recently demonstrated that stimulating iNKT cells in vivo with the specific synthetic ligand alpha-GalCer served to significantly enhance immune responses to protein-based vaccines. We have demonstrated that co-injection of iNKT cell agonists together with antigenic proteins enhances antigen-specific T cell responses. This enhancement is dependent on the involvement of iNKT cells and CD1d molecules and requires CD40 signalling. Thus, iNKT cells exert a significant influence on the efficacy of immune responses to soluble antigen by modulating DC function, as recently reviewed. Our results are consistent with the general concept that there is considerable immunostimulatory power in the integration of iNKT-mediated and TLR-mediated signals to DCs (Salio et al. 2007; McCarthy et al. 2007). Understanding this level of regulation will be important in designing appropriate, and hence effective, vaccines.
More recently, in collaboration with Facundo Batista (Cancer Research Institute), we have started to analyse the cross-talk between iNKT cells and B cells (Barral et al. 2010).
We previously developed two novel protocols for the refolding of denatured CD1 molecules, based either on the use of short mono-alkyl detergent molecules or on oxidative refolding chromatography. Techniques developed in the laboratory have enabled the use of ‘refolded’ CD1 molecules to monitor the frequency and phenotype of NKT cells in health and disease. Together with knowledge of the crystal structures of CD1d and CD1b loaded with different lipid antigens (solved in collaboration with Prof. E. Y. Jones, University of Oxford) it has been possible to study both in vitro and in vivo activation of NKT cells, and their effect on the adaptive immune responses.
3) Clinical Trial Programme in Melanoma Patients
My group has been developing a very active clinical trial programme to translate our preclinical vaccination strategies into phase I/II clinical trials and several cancer vaccines are currently being compared in the clinic.