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

项目摘要/摘要 T细胞在对感染和癌症的免疫反应中发挥着核心作用。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，或指示免疫系统的其他组件 攻击目标。需要严格控制T细胞令人敬畏的破坏力，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9个这样的配体 已确认身份。它们与T细胞上的受体结合，抑制T细胞的增殖和激活。有趣的是，许多人 不同类型的肿瘤细胞利用这些配体来逃避T细胞的攻击。最近，阻止这种相互作用的抗体 这些配体和它们的受体之间的关系已经被开发出来，以增强对癌症的免疫反应。 这些所谓的免疫检查点阻断药物已经成功地控制了一些人的肿瘤 患者，但总体应答率仍然很低。其中一个原因可能是大多数药物针对的是 只有一种免疫检查点配体的受体，而癌细胞可能表达许多不同的 配基的类型。目前，靶向更多受体是困难的，因为其中五个受体 配体尚未确定。识别它们的受体的一个主要挑战是它们与它们的配体结合 目前可用的方法非常薄弱，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、高灵敏的基于细胞的方法来识别五个孤儿配体的受体。这个 该方法的可行性将使用已知相互结合的模型配体和受体进行测试。 我们将使用基于细胞的方法来筛选跨膜蛋白集合和已识别的受体 候选人将接受测试，以确定他们绑定孤儿配体的能力。使用我们的方法识别受体 应该有助于理解B7家族免疫检查点配体是如何控制T细胞反应的，并可能作为 针对癌症的免疫检查点阻断疗法的新靶点。

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.