Pioneering a novel cancer targeting glyco-immunotherapy strategy

Background: Human cells are coated in a thick layer of sticky sugars called the glycocalyx. Uniquely cancer cells are covered with an excess of the human 'sialic acid' sugar Neu5Ac, and this has been shown to 'camouflage' the cells from the immune system. However, 2 million years ago a hydroxylated form of this sugar known as Neu5Gc was also present on human cells, but evolutionary selection drove inactivation of the gene required for conversion of Neu5Ac to an ancestral sialic acid, and this resulted in the loss of the ancestral sugar from the surface of human cells. Following this selection event, humans have developed circulating antibodies against this sugar.

Objectives: The aim of the project is to resurrect this ancestral sugar specifically in prostate cancer cells using antibody-targeted gene delivery. This strategy would aim to unleash the immune system's existing antibodies to kill the cancer cells, constituting a completely novel approach to cancer immunotherapy.

Experimental approach: Using novel chemical glyco-biology methods1,2 the student will contribute to the design of prostate cancer-cell specific gene delivery systems. The functional activity of these tools will be tested on well-established Prostate cancer (PCa) cell-lines, using a combination of flow cytometry, glycan mass spectrometry and immunofluorescence to determine the extent of cell surface glycan reengineering. Validation of the best delivery system will then follow using in vitro culture of primary prostate-isolated tumour cells and spheroids. This is a cross-disciplinary project primarily based at the University of York in the labs of Dr Martin Fascione (https://www.york.ac.uk/chemistry/staff/academic/d-g/mfascione/; Chemistry) and Dr Nathalie Signoret (https://www.york.ac.uk/biology/research/molecular-cellular-medicine/signoret/; Immunology, Hull York Medical School), and working collaboratively with Prof Craig Robson (https://www.ncl.ac.uk/medical-sciences/people/profile/cnrobson.html; Newcastle University Centre for Cancer). The student will train in aspects of organic chemistry, immunology and cancer cell biology specifically developing skills in glycoscience, protein bioconjugation, molecular biology, advanced cell imaging techniques and flow cytometry. The project would suit a candidate with an interest in translational science and any of chemical biology, glycoscience, immunology and/or cancer biology.

Novelty and Timeliness: In the last decade treatment of cancer has been revolutionised by antibody delivery of small molecule drugs and subsequently by cancer immunotherapy strategies which coopt the patient's own immune system to fight the cancer. For the first time we aim to harness aspects of both these field defining strategies simultaneously through re-engineering of cell surface glycans.