The Role of Physical Membrane Properties in Tumour Cell Resistance to Perforin

物理膜特性在肿瘤细胞对穿孔素的抵抗中的作用

• 批准号: MR/V009702/1
• 负责人: Bart Hoogenboom
• 金额: $ 81.34万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009702%2F1
• 关键词: Role; Physical; Membrane; Properties; Tumour

To kill virus-infected and cancer cells, the human immune system can use white blood cells that expose their targets to a mixture of toxic proteins. This is exploited by so-called cancer immunotherapies, which induce the immune system to more effectively target tumours. However, the success of these therapies strongly depends on the type of cancer and can be remarkably variable - even for the same type of cancer - from one patient to the other, for reasons that remain poorly understood.In the mix of proteins secreted by these white blood cells, an essential protein is perforin, which punches holes in the target cells. We have only recently discovered how the white blood cells are protected against the perforin they secrete, preventing them from being damaged every time they kill a target (e.g., a cancer cell). This protection resides in the physical properties of the membrane that surrounds the white blood cells, in particular in how the fatty acid molecules ("lipids") in the membrane are packed and what electric charge they have at the membrane surface.With this project, we aim to investigate if a similar protection may be used by cancer cells, to protect them against perforin and to thus reduce the efficiency at which they are cleared by the immune system. If this is the case, this can be used as an inspiration for strategies that enhance the efficacy of cancer immunotherapies and/or as a way to test patient resistance to such therapies before they are treated.

为了杀死病毒感染的细胞和癌细胞，人类免疫系统可以使用白细胞，将其目标暴露于有毒蛋白质的混合物中。所谓的癌症免疫疗法利用了这一点，诱导免疫系统更有效地针对肿瘤。然而，这些疗法的成功在很大程度上取决于癌症的类型，并且即使对于同一类型的癌症，从一个患者到另一个患者也可能存在显着差异，其原因仍知之甚少。白细胞中的一种必需蛋白质是穿孔素，它可以在靶细胞上打孔。我们最近才发现白细胞如何受到保护，免受它们分泌的穿孔素的影响，从而防止它们在每次杀死目标（例如癌细胞）时受到损害。这种保护作用在于白细胞周围膜的物理特性，特别是膜中脂肪酸分子（“脂质”）的堆积方式以及它们在膜表面具有的电荷。通过这个项目，我们的目的是研究癌细胞是否可以使用类似的保护，以保护它们免受穿孔素的侵害，从而降低免疫系统清除它们的效率。如果是这种情况，这可以作为增强癌症免疫疗法疗效的策略的灵感和/或作为在治疗前测试患者对此类疗法的抵抗力的方法。