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

为了杀死病毒感染的细胞和癌细胞，人类免疫系统可以利用白细胞将它们的目标暴露在有毒蛋白质的混合物中。这被称为癌症免疫疗法，诱导免疫系统更有效地靶向肿瘤。然而，这些疗法的成功在很大程度上取决于癌症的类型，并且可能在不同的患者之间存在显著的差异——即使是同一种癌症，原因仍然知之甚少。在这些白细胞分泌的蛋白质混合物中，一种必需的蛋白质是穿孔蛋白，它可以在目标细胞上打孔。直到最近，我们才发现白细胞是如何免受它们分泌的穿孔素的侵害，从而防止它们在每次杀死目标（例如癌细胞）时受到破坏的。这种保护存在于围绕白细胞的膜的物理特性中，特别是膜中的脂肪酸分子（“脂质”）是如何被包装的，以及它们在膜表面带什么电荷。在这个项目中，我们的目标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，从而降低它们被免疫系统清除的效率。如果是这样的话，这可以作为提高癌症免疫疗法疗效的策略的灵感和/或作为在治疗之前测试患者对此类疗法的耐药性的一种方法。

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.