Enhancement of dendritic cell vaccine efficiency against pancreatic cancer by MSK

描述（由申请方提供）：本项目旨在检验一个中心假设，即沉默树突状细胞中的主免疫负调节因子MSK（促分裂原和应激激活蛋白激酶）将使其被MSLN-VLP刺激完全激活，从而显著增加主动免疫应答并消除抑制性免疫应答。这将增加DC疫苗在小鼠模型中针对胰腺癌的治疗效率。提出了两个具体的目标：1）确定MSK在DC抗原呈递，细胞因子产生和T细胞刺激中的关键作用。我们假设阻断DCs中的MSK 1和MSK 2基因将增强DC活化和Ag呈递特性;它还将减少免疫抑制性细胞因子的产生，并减少Treg的产生。2)目的：研究MSK沉默和MSLN-VLP刺激的DC疫苗在胰腺癌小鼠模型中的主动免疫应答诱导和治疗效果。我们假设，具有MSK沉默和MSLN-VLP刺激的DC疫苗可以在原位植入胰腺癌小鼠模型中诱导更强的主动免疫应答并有效地控制胰腺癌进展。总的来说，我们希望这些研究有助于我们对胰腺癌疫苗开发的认识，并直接影响人类胰腺癌的治疗。 公共卫生相关性：胰腺癌的发病率与死亡率相当，迫切需要新的胰腺癌治疗方法。本课题旨在研制一种新型的胰腺癌病毒样颗粒（virus-like particle，VLP）刺激的树突状细胞（dendritic cell，DC）免疫疫苗。通过阻断DC中的免疫抑制因子，该疫苗可能具有增强的处理肿瘤抗原的能力，并产生肿瘤特异性应答偏向性免疫，从而增强VLP免疫治疗对胰腺癌的功效。

DESCRIPTION (provided by applicant): This project is designed to test a central hypothesis that silencing the master immune negative regulator MSK (mitogen- and stress-activated protein kinase) in dendritic cells will allow them to be fully activated by MSLN-VLP stimulation, significantly increasing the active immune response and eliminating the suppressive immune response. This would increase the therapeutic efficiency of the DC vaccine against pancreatic cancer in the mouse model. Two specific aims are proposed: 1) To determine critical roles of MSKs in DC antigen presentation, cytokine production, and T cell stimulation in vitro. We hypothesize that blocking the MSK1 and MSK2 genes in DCs will enhance DC activation and the Ag-presentation property; it will also reduce immune suppressive cytokine production, and reduce Treg production. 2) To determine the active immune response induction and therapeutic efficacy of DC vaccine with MSK silencing and MSLN-VLP stimulation in the mouse models of pancreatic cancer. We hypothesize that DC vaccine with MSK silencing and MSLN-VLP stimulation could induce stronger active immune responses and efficiently control pancreatic cancer progression in the orthotopic implant pancreatic cancer mouse model. Overall, we expect these studies to contribute significantly to our knowledge of pancreatic cancer vaccine development with immediate implications in therapeutic treatment of human pancreatic cancer. PUBLIC HEALTH RELEVANCE: The incidence of pancreatic cancer remains equal to the mortality rate, new approaches to the treatment of pancreatic cancer are urgently needed. This project is designed to develop a novel virus-like particle (VLP) stimulated dendritic cell (DC) immunotherapeutic vaccine for pancreatic cancer. By blocking the immune inhibitory factors in DC, this vaccine may have an enhanced ability to process tumor antigens and generate tumor-specific response biased immunity, thereby enhancing the efficacy of VLP immunotherapy against pancreatic cancer.