Tumour Immunology

We are pursuing several different lines of investigation with the common goal of improving treatment strategies for cancer. The ability of cancer cells to avoid destruction by the immune system means that as yet there is no effective treatment. We know that in several different types of cancer there are increased numbers of cells called myeloid suppressor cells (MDSC) that suppress the immune system, and therefore allow cancer cells to continue to grow and divide. We also know that another kind of immune cells - invariant natural killer T (iNKT) cells –monitor malignant cells and decrease the numbers of circulating MDSCs in melanoma patients, thus restoring the immune response to cancer cells. These iNKT cells are very important because they form a “bridge” between the part of the immune system that recognises foreign proteins and the part that destroys abnormal cells. By studying the behaviour of iNKT cells we aim to find ways of increasing their activity in a controlled way, and use them to “jump-start” immune responses to tumour cells. Our clinical trial program is presently translating preclinical findings into phase I and II clinical trials of cancer vaccine candidates.

Goals To develop vaccination strategies to enhance tumour specific T cell responses. By bridging the innate and adaptive arms of the immune system invariant NKT (iNKT) cells can be harnessed to jump-start antigen-specific immune responses. Stimulation of iNKT cells in vivo with the specific synthetic ligands results in significantly enhanced immune responses to protein-based vaccines. Further, activation of human dendritic cells (DC) by toll-like receptor (TLR) agonists modulates the lipid biosynthetic pathway, resulting in enhanced recognition of CD1d associated lipids by iNKT cells. Thus, iNKT cells significantly influence the efficacy of immune responses to soluble antigen by modulating DC function, supporting the concept that there is substantial immunostimulatory power in the integration of iNKT cell- and TLR-mediated signals to dendritic cells. We have characterized by structural (1), kinetic (2), and functional (2,3) studies a novel family of NKT cell agonists (4), and more recently shown that iNKT cells modulate the suppressive activity of neutrophils (5). A large proportion of melanoma cells produces the major acute-phase reactant serum amyloid A-1 (SAA-1), one of the first and most abundant proteins secreted during the physiological response to infection and injury. By binding to formyl-peptide receptor 2 expressed by neutrophils, SAA induces them to secrete IL-10 which suppresses the T cell response. CD1d- and CD40- dependent interaction of neutrophils with iNKT cells ameliorates this suppressive activity indicating a pivotal role anti-tumour responses (5). Tumours also evade immune responses by depleting tryptophan via the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase (IDO). Such depletion induces regulatory T cells and inhibits effector T cells. Local tryptophan depletion is overcome by IDO positive tumour cells by the expression of a novel amino acid transporter distinct from system L (6) - this increases tryptophan entry into IDO positive tumours, depleting the microenvironment further. This additional tryptophan transporter could be the key to pharmacological inhibition of IDO mediated tumour escape (6). The ability to direct homing of antigen specific T cells to specific tumour tissue is crucial to anti-tumour strategies. We have extended the notion that production of retinoic acid (RA) by dendritic cells (DCs) is critical for development of gut-tropic immune responses by demonstrating that Prostaglandin E2 blocks expression of retinal dehydrogenases (RALDH) - enzymes responsible for converting vitamin A into RA - abrogating the ability to induce CCR9 expression upon T cell priming (7). Future research plans Future work aims to characterize further strategies to enhance immune responses and to modify the tumour microenvironment, with emphasis on: (a) the role of iNKT cells in bridging the adaptive and innate immune responses; (b) the plasticity of myeloid cells in regulating tumour specific immune responses; (c) the role of tryptophan degrading enzymes in upregulating higher affinity tryptophan transporters; and (d) vaccine clinical trials in melanoma patients. References: (1) Koch et al. 2005 Nature Immunol 6: 819 (2) McCarthy et al 2007 J Exp Med 204: 1131 (3) Salio et al 2007 Proc Natl Acad Sci 104:20490 (4) Silk et al 2008 J Immunol 180: 6452 (5) De Santo et al 2010 Nature Immunol 11: 1039 (6) Silk et al 2011 J Immunol 187: 1617 (7) Stock et al 2011 J Exp Med 208: 761.