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

实际上，细胞表面携带的所有蛋白质都带有糖；这些组合的结构被称为糖蛋白。这些糖或聚糖是蛋白质功能的基础，并参与细胞与细胞和细胞与环境的相互作用。重要的是，这些糖蛋白上的糖随着癌症的发展而变化，因此，在癌症中，糖蛋白可以与一组新的蛋白质和细胞相互作用。我们之前已经证明，乳腺癌表达的一种特殊的糖蛋白MUC1携带异常的聚糖，使其能够与浸润肿瘤的特定免疫细胞（称为单核细胞和巨噬细胞）结合。一旦结合发生，单核细胞和巨噬细胞就会发生变化：单核细胞分泌诱导肿瘤生长的因子并招募更多的免疫细胞，而巨噬细胞则成为“肿瘤相关巨噬细胞”，这是一种与侵袭和预后不良相关的细胞。在这个项目中，我们计划：a)确定这些特定的单核细胞和巨噬细胞在乳腺癌中的常见程度，并确认它们与MUC1的特定糖型相关。b)确定MUC1诱导这些巨噬细胞表达的基因是否与预后相关。c)确定抑制MUC1与单核细胞和巨噬细胞的相互作用是否可以作为乳腺癌和其他癌症患者的潜在治疗方法。MUC1与单核细胞和巨噬细胞上的受体相互作用作为抑制先天免疫反应的“检查点”。我们假设，阻断这种相互作用应该会释放“刹车”，让免疫系统识别肿瘤。我们计划使用一系列体外技术来实现这些目标，我们的结果应该为这种新的治疗方法的临床前测试铺平道路。

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.