The MUC1-ST/Siglec-9 innate check point axis in cancer: prevalence, prognostic significance and potential therapeutics.

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Virtually all proteins carried on the surface of cells are decorated with sugars; these combined structures are known as glycoproteins. These sugars, or glycans, are fundamental to the function of the protein and are involved in cell:cell and cell:environment interactions. Importantly the sugars on these glycoproteins change as cancers develop and so, in cancer, the glycoproteins can interact with a new set of proteins and cells. We have previously shown that one particular glycoprotein, MUC1, expressed by breast cancers carries aberrant glycans that allow it to bind to specific immune cells, called monocytes and macrophages that infiltrate the tumour. Once the binding takes place the monocytes and macrophages change: the monocytes secrete factors that induce tumour growth and recruit more immune cells, and the macrophages become "tumour-associated macrophages" a type of cell that is associated with invasion and a poor prognosis.In this project we plan to:a) Determine how common these particular monocytes and macrophages are in breast cancer and to confirm that they are associated with a particular glycoform of MUC1.b) Determine if the genes expressed by these macrophages induced by MUC1 is associated with prognosis.c) Determine if inhibiting the interaction between MUC1 and the monocytes and macrophages can be used as a potential therapy for breast and other cancer patients. The interaction of MUC1 and the receptor on monocytes and macrophages acts as a "checkpoint" to inhibit the innate immune response. We hypothesize that blocking the interaction should release the brakes and allow for the immune system to recognise the tumour. We plan to use of series of in vitro techniques to address these aims and our results should pave the way for preclinical testing of this new therapeutic approach.