Identify receptors for B7 family immune checkpoint orphan ligands using a novel cellbased approach

项目概要/摘要 T细胞是对感染和癌症的免疫反应的核心参与者。一旦被抗原激活，T细胞 能够直接杀死受感染的细胞和癌细胞，或指导免疫系统的其他成分， 攻击目标。T细胞可怕的破坏力需要严格控制，以避免 对正常组织的附带损害和预防自身免疫性疾病。一种重要的控制机制 是通过B7家族免疫检查点配体抑制T细胞活性。到目前为止，已经有九种这样的配体被发现。 鉴定它们与T细胞上的受体结合以抑制T细胞增殖和活化。有趣的是，许多 不同类型的肿瘤细胞选择这些配体来逃避T细胞的攻击。最近，阻断这种相互作用的抗体 已经开发了这些配体和它们的受体之间的相互作用以增强对癌症的免疫应答。 这些所谓的免疫检查点阻断药物已经成功地控制了一些肿瘤。 患者，但总体反应率仍然很低。原因之一可能是大多数药物的靶点 仅一种免疫检查点配体的受体，而癌细胞可以表达许多不同的免疫检查点配体。 配体的类型。目前，靶向额外的受体是困难的，因为五种受体的受体是不稳定的。 配体还有待鉴定。识别它们的受体的一个主要挑战是它们与配体结合 非常弱，目前可用的方法没有足够的灵敏度。为了克服这一点，我们建议 开发一种新的和高度敏感的基于细胞的方法来识别五种孤儿配体的受体。的 将使用已知相互结合的模型配体和受体来测试该方法的可行性。 我们将使用基于细胞的方法来筛选跨膜蛋白集合和所鉴定的受体 将测试候选物结合孤儿配体的能力。使用我们的方法鉴定的受体 应该有助于理解B7家族免疫检查点配体如何控制T细胞反应，并可能作为 免疫检查点阻断治疗癌症的新靶点。

PROJECT SUMMARY/ABSTRACT T cells are central players in immune responses to infections and cancer. Once activated by antigens, T cells are able to directly kill infected cells and cancer cells, or direct other components of the immune system to attack targets. The awesome destructive power of T cells needs to be tightly controlled in order to avoid collateral damages to normal tissues and to prevent autoimmune diseases. An important mechanism of control is to inhibit T cell activities through B7 family immune checkpoint ligands. To date nine such ligands have been identified. They bind to receptors on T cells to inhibit T cell proliferation and activation. Interestingly, many types of tumor cells co-opt these ligands to evade T cell attack. Recently, antibodies that block the interactions between these ligands and their receptors have been developed to enhance immune response to cancer. These so-called immune checkpoint blockade drugs have been successful in controlling tumors in some patients, but the overall response rates are still low. One of the reasons may be that most of the drugs target the receptor of only one of the immune checkpoint ligands while cancer cells may express many of the different types of ligands. Currently, targeting additional receptors are difficult because the receptors for five of the ligands have yet to be identified. A major challenge for identifying their receptors is that they bind their ligands very weakly and currently available methods do not have enough sensitivity. To overcome this, we propose to develop a novel and highly sensitive cell-based approach to identify receptors for the five orphan ligands. The feasibility of the approach will be tested using model ligands and receptors that are known bind to each other. We will use the cell-based approach to screen transmembrane protein collections and the identified receptor candidates will be tested for their abilities to bind the orphan ligands. Receptors identified using our approach should help understand how B7 family immune checkpoint ligands control T cell responses and may serve as new targets for immune checkpoint blockade therapies against cancer.