Pioneering a novel cancer targeting glyco-immunotherapy strategy

背景：人类细胞被一层厚厚的粘性糖衣所覆盖，这层糖衣被称为糖萼。独一无二的是，癌细胞上覆盖着过量的人类唾液酸糖Neu5Ac，这已经被证明可以掩盖免疫系统中的细胞。然而，200万年前，这种糖的一种羟化形式Neu5Gc也存在于人类细胞中，但进化选择导致Neu5Ac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。在这一选择事件之后，人类已经产生了针对这种糖的循环抗体。目的：该项目的目的是通过抗体靶向的基因传递，在前列腺癌细胞中恢复这种祖传的糖类。这一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学生将对前列腺癌细胞特异性基因传递系统的设计做出贡献。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、多聚糖质谱和免疫荧光相结合的方法来确定细胞表面多糖重组的程度。随后将使用原代前列腺分离的肿瘤细胞和球体的体外培养来验证最佳输送系统。这是一个跨学科的项目，主要设在约克大学(马丁·法西奥尼(https://www.york.ac.uk/chemistry/staff/academic/d-g/mfascione/；化学博士和纳塔莉·西格诺雷特博士，赫尔·约克医学院(https://www.york.ac.uk/biology/research/molecular-cellular-medicine/signoret/；免疫学博士)的实验室，并与克雷格·罗布森教授((https://www.ncl.ac.uk/medical-sciences/people/profile/cnrobson.html；纽卡斯尔大学癌症中心)合作)。学生将接受有机化学、免疫学和癌细胞生物学方面的培训，特别是开发糖科学、蛋白质生物偶联、分子生物学、先进细胞成像技术和流式细胞术方面的技能。该项目将适合对翻译科学和任何化学生物学、糖科学、免疫学和/或癌症生物学感兴趣的候选人。新颖性和及时性：在过去的十年里，通过小分子药物的抗体传递以及随后的癌症免疫治疗策略，癌症的治疗已经发生了革命性的变化，癌症免疫治疗策略利用患者自己的免疫系统来对抗癌症。第一次，我们的目标是通过细胞表面多糖的重新设计，同时利用这两种领域定义策略的各个方面。

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.