Pioneering a novel cancer targeting glyco-immunotherapy strategy

背景：人类细胞被一层厚厚的粘性糖包被，称为糖萼。独特的是，癌细胞被过量的人类“唾液酸”糖Neu 5Ac覆盖，这已被证明可以“伪装”免疫系统的细胞。然而，200万年前，这种糖的羟基化形式称为Neu 5Gc也存在于人类细胞中，但进化选择驱使Neu 5Ac转化为祖先唾液酸所需的基因失活，这导致人类细胞表面的祖先糖丢失。在这种选择事件之后，人类已经产生了针对这种糖的循环抗体。目的：该项目的目的是使用抗体靶向基因递送在前列腺癌细胞中特异性地复活这种祖先糖。这种策略旨在释放免疫系统现有的抗体来杀死癌细胞，构成一种全新的癌症免疫治疗方法。实验方法：使用新的化学糖生物学方法1，2学生将有助于前列腺癌细胞特异性基因传递系统的设计。这些工具的功能活性将在成熟的前列腺癌（PCa）细胞系上进行测试，使用流式细胞术、聚糖质谱和免疫荧光的组合来确定细胞表面聚糖重组的程度。然后将使用原代前列腺分离的肿瘤细胞和球状体的体外培养来验证最佳递送系统。这是一个跨学科项目，主要基于约克大学的Martin Fascione博士（https：//www.york.ac.uk/chemistry/staff/academic/d-g/mfascione/; Chemistry）和Nathalie Signoret博士（https：//www.york.ac.uk/biology/research/molecular-cellular-medicine/signoret/; Immunology，船体York Medical School）的实验室，并与克雷格Robson教授（https：//www.ncl.ac.uk/medical-sciences/people/profile/cnrobson.html;纽卡斯尔大学癌症中心）合作。学生将在有机化学，免疫学和癌细胞生物学方面进行培训，特别是在糖科学，蛋白质生物缀合，分子生物学，先进的细胞成像技术和流式细胞术方面发展技能。新奇和及时性：在过去的十年中，癌症的治疗已经通过小分子药物的抗体递送以及随后的癌症免疫治疗策略而发生了革命性的变化，这些策略利用患者自身的免疫系统来对抗癌症。我们的目标是第一次利用这两个方面的领域定义的战略，同时通过重新设计细胞表面聚糖。

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.