早期诊断困难，易耐药和高转移性是胰腺癌治疗的主要临床挑战。并且，胰腺癌患者的免疫治疗联合化疗效果并不理想。其主要原因是胰腺癌组织中致密的间质屏障阻碍药物在瘤内的递送和分布, 且肿瘤微环境中的免疫抑制进限制了T细胞的免疫杀伤功能。前期工作中，本团队己研制出胰腺癌和肿瘤间质细胞的多种靶向氧化铁纳米药物载体和纳米PD-L1抑制剂，此类靶向纳米药物可突破肿瘤间质屏障, 实现药物的高效递送。它们递送到肿瘤后可促进免疫细胞浸润, 提高低免疫性胰腺癌转化为高免疫性肿瘤的机率，从而提升疗效。在此基础上，本项目提出制备靶向纳米粒子递送化疗药物和免疫检查点阻断剂，并对胰腺癌小鼠模型进行联合治疗以及作用机理研究，为开发新的联合疗法提供依据。本课题通过对比不同靶向纳米药物对胰腺癌细胞的杀伤效果，以及对肿瘤微环境的免疫调控作用,优化胰腺癌的靶向纳米药物和纳米免疫检查点抑制联合治疗，从而阐明其作用机制。

Inability of early detection, resistance to therapy, and high incidence of tumor metastases are the major clinical challenges for the treatment of pancreatic cancer. Although the combination of immune checkpoint therapy with chemotherapy has shown promising therapeutic responses in many types of human cancers, pancreatic cancer patients had a poor response to the immunotherapy. Increasing evidence shows that the dense stroma barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of therapeutic antibodies. Stromal physical and immune suppressive biological barriers in tumor microenvironment further limit the number and function of cytotoxicity CD8+ T cells and prevent infiltration of cytotoxic T cells in the tumor. Results of clinical studies have shown that systemic administration of anti-PD-1/PD-L1 antibodies induced adverse effects in cancer patients, including severe cardiotoxicity. The objective of the proposed study is to develop a new combination therapy using targeted nanoparticles for delivery of drug and immune checkpoint blocking agents. Our group has developed receptor targeted magnetic iron oxide nanoparticle (IONP) drug carriers that target to cellular receptors highly expressed in pancreatic cancer and tumor stromal cells. Systemic administrations of those targeted nanoparticles carrying drugs enabled overcoming stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in pancreatic cancer patient tissue derived xenograft (PDX) and transgenic mouse pancreatic tumor models. Notably, targeted delivery of a high level of IONP-drugs into mouse pancreatic tumors promoted infiltration of immune cells, especially CD8+ cytotoxic T cells, that converted an immunoscore “cold” pancreatic cancer into a pro-immune “hot” tumor. Therefore, we hypothesize that targeted therapy using our unique receptor targeted nanoparticle-drugs effectively kill tumor cells while releasing neoantigens and promoting a proimmune microenvironment. A further combination with an immune checkpoint agent, a nanoPD1 that inhibits PD-L1, can enhance tumor specific cytotoxic T cell response and reduce systemic side effects. In the proposed study, we will investigate and compare the immune modulating effects of the nanoparticle-drugs that target different cellular receptors in a Kras/p53 transgenic mouse pancreatic tumor model. We will then determine if the combination of targeted nanoparticle-drug with nanoPD1 enhances therapeutic response in the mouse tumor model. Finally, we will elucidate mechanisms of the action of the combination of targeted therapy with nano-PD1 by histological, immunofluorescence, and immunological analysis of tumor tissues following treatments. Results of the proposed study will provide important mechanistic information for further development of this novel combination therapy for effective treatment of pancreatic cancer.