免疫检查点单抗是最成功的肿瘤免疫治疗方法，但临床试验数据表明，目前的免疫检查点单抗对胰腺导管腺癌（PDA）均没有治疗作用。原因可能与PDA的特殊微环境有关，而PDA微环境最大的特点就是局部肿瘤相关成纤维细胞（CAF）大量增生，参与肿瘤免疫编辑。B7-H5/CD28H是课题组发现的新型免疫共刺激通路，前期研究发现PDA标本中肿瘤细胞B7-H5特异性缺失伴随局部CD8+T细胞CD28H的丢失，而CAF可以调控其表达。提示这一共刺激信号在PDA特殊微环境的免疫编辑过程中发挥重要作用。基于此，本课题拟利用临床样本分析来明确这一作用，并利用原代PDA细胞、CAF与CD8+T细胞共培养及NSG小鼠PDA模型，系统研究三种细胞互相作用对B7-H5/CD28H信号通路的调控，并探讨可能机制；同时明确CD28H激动单抗或联用PD-1抑制剂对PDA的治疗作用，以期为临床PDA免疫治疗提供全新靶点和潜在方案。

Immune checkpoint blockade is believed the most effective strategy for immunotherapy of cancer. However, current checkpoint blocking antibodies have not been proved useful in pancreatic ductal adenocarcinoma (PDA) by clinical trials. The microenvironment of PDA is one probable reason. The extensive proliferation of cancer-associated fibroblasts (CAFs), which participate in immunological editing, is a prominent characteristic of PDA environment. We previously found a novel T cell costimulatory pathway B7-H5/CD28H, and figured out that B7-H5 molecules were lost in PDA cancer cells companied with the absence of CD28H in the regional CD8+ T cells. In addition, CAFs could regulate the expression of CD28H. These results suggested the important roles of the B7-H5/CD28H pathway in immunological editing of PDA environment. This project plans to verify this hypothesis by using clinical specimens. Further, we will use primary PDA cells, CAFs, CD8+ T cells, and NSG mouse model of PDA to study the interaction of these cells and their regulatory roles of B7-H5/CD28H pathway. Meanwhile, we will test the effectiveness of CD28H stimulatory antibody and its combination with PD-1 inhibitor. The results of project may provide new targets and strategies for PDA treatment.