Removing sialic acid ligands of CD28 to enhance T cell cancer immunotherapy

总结 T细胞在适应性免疫系统中起核心作用，并响应于T细胞受体（TCR）而被激活。 识别抗原呈递细胞的主要组织相容性复合体（MHC）上负载的抗原 （APC）。为了完全实现T细胞效应器功能，通过接合提供了必需的“第二信号”， T细胞共刺激受体CD 28及其B7配体（CD 80/CD 86）在APC上的表达。我们最近 表明T细胞和APC上的唾液酸抑制了CD 28与CD 80/CD 86的结合， 唾液酸与唾液酸酶一起增强T细胞增殖。唾液酸的去除也与程序化的 细胞死亡蛋白-1（α PD 1）检查点抑制剂阻断，用于衰竭T细胞的功能复苏。在这 项目，我们将开发双功能α PD 1-唾液酸酶缀合物，预计将联合收割机的好处， PD 1阻断，去除CD 28的唾液酸配体，促进与B7配体的结合，并增强CD 28的免疫原性。 T细胞活化。我们将在癌症动物模型中评估这些试剂的治疗潜力， 激活耗尽的T细胞并抑制癌症进展。

Summary T cells play a central role in the adaptive immune system and are activated in response to T cell receptor (TCR) recognition of antigen loaded on the major-histocompatibility complex (MHC) of antigen presenting cells (APCs). In order to fully achieve T cell effector function, an essential “second signal” is provided by engagement of the T cell costimulatory receptor CD28 with its B7 ligands (CD80/CD86) on the APC. We recently demonstrated that sialic acids on T cells and APCs dampen CD28 binding to CD80/CD86 and that removal of sialic acids with sialidase enhances T cell proliferation. Sialic acid removal is also synergistic with programmed cell death protein-1 (αPD1) checkpoint inhibitor blockade for functional revival of exhausted T cells. In this project, we will develop bifunctional αPD1-sialidase conjugates that are expected to combine the benefits of PD1 blockade with removal of sialic acid ligands of CD28 to promote engagement with B7 ligands and enhance T cell activation. We will evaluate these reagents in animal models of cancer for their therapeutic potential to invigorate exhausted T cells and suppress cancer progression.