Congratulations to our staff members who have been awarded research funding by the Health Research Council of New Zealand (HRC). Associate Professor Keith Ireton (with Dr Mihnea Bostina) has been provided a grant to investigate the role of host exocytosis in Listeria. Associate Professor Alex McLellan has received an explorer grant to look at T cell migration and activation.
Listeria monocytogenes is a potentially deadly cause of food-borne illnesses including meningitis and abortion. Listeria is internalised into human cells and spreads from infected cells to neighbouring healthy cells by generating 'protrusions' - bacteria encased in finger-like projections of the host plasma membrane. How protrusions form and elongate to allow cell-to-cell spread is poorly understood. This proposal tests the novel hypothesis that Listeria subverts the function of a human complex called the exocyst to direct the insertion of host-derived membrane that fuels the growth of protrusions.
In this proposal, we will exploit the low pH environment of solid tumours to enhance T cell immunotherapy. T cells will be genetically modified with constructs that enhance T cell migration to the low pH environment of tumours and that activate T cells to destroy cancer cells. We will fuse domains of a proton-sensing G-protein coupled receptor (GPCR) to the intracellular signalling domains of a GPCR chemokine-receptor. This will effectively translate suppressive, low pH signalling into migratory and activatory signals for anti-cancer T cells. We propose that chimeric GPCR-modified T cells will be highly effective at infiltrating and destroying solid tumours and represent a novel paradigm for improving immunotherapy for traditionally hard to treat cancers.