- Infection and Immunology
- Daniel Ajzensztejn
- Laura Barker
- Sarah Booth
- Ji-Li Chen
- Amina Dawoodji
- Hemza Ghadbane
- Uzi Gileadi
- Madeleine Hipp
- John-Paul Jukes
- Amy Kenyon
- Elina Lipina
- Rosanna McEwan-Smith
- Giorgio Napolitani
- Nicolas Platt
- Mariolina Salio
- Dawn Shepherd
- Jonathan Silk
- Andrea Tarlton
- Ron Wolchinsky
- Silk Jonathan D, Lakhal Samira, Laynes Robert, Vallius Laura, Karydis Ioannis, Marcea Cornelius, Boyd C AR, and Cerundolo Vincenzo (2011) IDO induces expression of a novel tryptophan transporter in mouse and human tumor cells. J Immunol, 187(4):1617-25.
- Stock Angus, Booth Sarah, and Cerundolo Vincenzo (2011) Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans. J Exp Med, 208(4):761-73.
- De Santo Carmela, Arscott Ramon, Booth Sarah, Karydis Ioannis, Jones Margaret, Asher Ruth, Salio Mariolina, Middleton Mark, and Cerundolo Vincenzo (2010) Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nat Immunol, 11(11):1039-46.
- De Santo Carmela, Salio Mariolina, Masri S H, Lee Laurel Y, Dong Tao, Speak Anneliese O, Porubsky Stefan, Booth Sarah, Veerapen Natacha, Besra Gurdyal S, Grone Hermann-Josef, Platt Frances M, Zambon Maria, and Cerundolo Vincenzo (2008) Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest, 118(12):4036-48.
- Barral Patricia, Polzella Paolo, Bruckbauer Andreas, van Rooijen Nico, Besra Gurdyal S, Cerundolo Vincenzo, and Batista Facundo D (2010) CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat Immunol, 11(4):303-12.
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: i) analysis of tumour-specific immune responses in melanoma patients and the role of the tumour micro-environment in hampering tumour-specific immune responses; ii) structural, kinetic and functional analyses of invariant NKT (iNKT) cell activation; iii) clinical trial vaccine programme in melanoma patients.
i) 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 presence of IL-10 secreting neutrophils in a large proportion of melanoma patients. These cells suppress proliferation and activity of tumour-specific T cell responses (De Santo et al. 2011). We have extended these results by demonstrating that binding of Serum Amyloid A (SAA) to Formyl-Peptide Receptor 2 controls the plasticity of neutrophil differentiation by triggering IL-10 synthesis and promoting their ability to interact with iNKT cells via CD1d molecules. CD1d and CD40 dependent interaction of IL-10 secreting neutrophils with iNKT cells results in reduced IL-10 and enhanced IL-12 production, thus limiting their suppressive activity (De Santo et al. 2011). The observation that melanomas promote differentiation of IL-10 secreting neutrophils by producing SAA highlights the importance of harnessing iNKT cells in therapeutic strategies to reduce the frequency of immunosuppressive neutrophils and to restore tumour specific immune responses.
In addition to optimise strategies to increase the frequency of tumour-specific T cells, it is important to characterise further the mechanisms that control the ability of antigen specific T cells to home to defined tissues, as this would facilitate the development of strategies to improve homing of T cells into different tumour types. Over the last 2 years, 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).
Recently we have been characterising a novel tryptophan transporter, up-regulated in cells expressing the tryptophan degrading enzyme indoleamine-2,3-dioxygenase (IDO) (Silk et al. 2011).
ii) 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 lpha-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.
iii) 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.
Polarization of NKT cell cytotoxic granules is modulated by the length of lipid antigens. McCarthy et al. J Exp Med. 2007 May 14;204(5):1131-44