Engineering synthetic adhesion receptors to enhance the sensitivity of therapeutic chimeric antigen receptors

T细胞是一种白色血细胞，它不断地在体内巡逻，寻找异常细胞。他们使用T细胞抗原受体（TCR）检测这些异常感染或癌细胞上称为“抗原”的分子。T细胞非常敏感：它们可以被细胞上存在的单一抗原激活。这种敏感性很重要，因为感染性生物体和癌细胞非常善于通过降低细胞表面抗原的数量来躲避T细胞。一种令人兴奋的癌症新疗法是重新编程患者的T细胞以靶向其癌症。这是通过使用基因工程在T细胞上表达嵌合抗原受体（汽车）来完成的。汽车具有结合抗原的部分和来源于TCR的部分，所述TCR将激活信号发送到T细胞中。它们允许患者的T细胞识别并杀死癌细胞。这种疗法对表达高水平某些抗原的白血病和淋巴瘤非常有效。然而，当癌细胞表面抗原水平较低时，许多患者会复发。这种逃避是可能的一个原因是汽车比TCR敏感得多，因此无法“看到”这些新的癌细胞。迫切需要增加汽车的敏感性以防止这些复发。更敏感的汽车也将允许CAR T细胞用于治疗更广泛的癌症。在这个项目中，我们将利用我们对TCR如此敏感的原因的理解来提高汽车的敏感性。对于T细胞表面上相对较小的TCR来说，很难“找到”其他细胞上的小靶抗原。T细胞使用一种称为CD 2的特殊进化的粘附受体，当它与靶细胞结合时，将T细胞和靶细胞膜定位在TCR与其靶抗原结合的正确距离处。这允许TCR快速扫描另一个细胞的抗原。我们假设CD 2将膜定位得太近而无法通过汽车进行最佳扫描，因为它们比TCR大。我们将设计并将CD 2的放大形式引入T细胞，并测试它们是否提高汽车的敏感性。我们将使用电子显微镜来证实，扩大CD 2改变T细胞和靶细胞膜之间的距离。这项工作应该使我们能够通过将扩大形式的CD 2引入细胞来改善CAR T细胞疗法，从而使它们能够识别具有低水平抗原的癌细胞。除了改善现有的针对B细胞癌症的CAR-T细胞治疗外，这应该允许开发新的CAR-T细胞治疗方法，以消除表达低水平靶抗原的癌症。

T cells are a type of white blood cell that continuously patrol the body in search of abnormal cells. They detect molecules called 'antigens' on these abnormal infected or cancerous cells using their T cell antigen receptors (TCRs). T cells are remarkably sensitive: they can become activated by the presence of a single antigen on a cell. This sensitivity is important because infectious organisms and cancer cells are very good at hiding from T cells by lowering the amount of antigen on their cell surface.An exciting new treatment for cancer is to re-programme a patient's T cells to target their cancer. This is done by using genetic engineering to express chimeric antigen receptors (CARs) on T cells. CARs have a part that binds an antigen and a part derived from the TCR that send an activating signal into the T cell. They allows a patient's T cells to recognise and kill their cancer cells. This therapy is very effective for leukemias and lymphomas expressing high levels of certain antigens. However, many patients relapse when cancer cells emerge that have lower levels of antigen on their surface. One reason that this escape is possible is that CARs are much less sensitive than TCRs and so are unable to 'see' these new cancer cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses. More sensitive CARs would also allow CAR T cells to be used in treating a wider variety of cancers.In this project we will use our understanding of why the TCR is so sensitive to improve the sensitivity of CARs. It is difficult for the relatively small TCR on the surface of T cells to 'find' what are also small target antigens on other cells. T cells use a specially-evolved adhesion receptor called CD2 that, when it binds to target cells, position the T cell and target cell membranes at precisely the right distance for the TCR to bind its target antigen. The allows the TCR to rapidly scan the other cell for antigens. We hypothesise that CD2 positions the membranes too closely for optimal scanning by CARs because they are bigger than the TCR. We will design and introduce into T cells enlarged forms of CD2 and test whether they improve the sensitivity of CARs. We will use electron microscopy to confirm that enlarging CD2 changes the distance between the T cell and the target cell membranes. This work should enable us to improve CAR T cell therapy by introducing enlarged forms of CD2 into the cells, thereby enabling them to recognise cancer cells with low levels of the antigen. In addition to improving existing CAR-T cell treatment for B cell cancers, this should allow new CAR-T cell treatments to be developed that eliminate cancers expressing low levels of target antigens.