Enhancement of dendritic cell vaccine efficiency against pancreatic cancer by MSK

MSK 增强树突状细胞疫苗对抗胰腺癌的功效

• 批准号: 7701010
• 负责人: Qizhi C. Yao
• 金额: $ 16.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-17 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701010
• 关键词: Antigen Presentation; Antigen-Presenting Cells; Antigens; CD58 gene; Cancer Etiology; Cancer Vaccine Related Development; Cancer Vaccines; DUSP1 gene; Data; Dendritic Cell Vaccine; Dendritic Cells; Dendritic cell activation; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Incidence; Interleukin-10; Knowledge; Maintenance; Malignant neoplasm of pancreas; Mitogens; Mus; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Phenotype; Process; Production; Property; RPS6KA5 gene; Radiation therapy; Reporting; Role; Site; Specificity; Spleen; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Burden; Vaccines; Virus-like particle; antigen processing; chemotherapy; cytokine; design; mesothelin; mortality; mouse model; novel strategies; novel virus; overexpression; public health relevance; response; stress activated protein kinase; tumor; tumor progression

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.

描述（由申请人提供）：该项目旨在测试一个中心假设，即沉默树突状细胞中的主免疫负调节因子 MSK（丝裂原和应激激活蛋白激酶）将使它们被 MSLN-VLP 刺激完全激活，显着增强主动免疫反应并消除抑制性免疫反应。这将提高 DC 疫苗在小鼠模型中针对胰腺癌的治疗效率。提出了两个具体目标：1) 确定 MSK 在 DC 抗原呈递、细胞因子产生和体外 T 细胞刺激中的关键作用。我们假设阻断 DC 中的 MSK1 和 MSK2 基因将增强 DC 的激活和 Ag 呈递特性；它还会减少免疫抑制细胞因子的产生，并减少 Treg 的产生。 2) 确定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反应诱导和治疗效果。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反应并有效控制胰腺癌进展。总体而言，我们预计这些研究将对我们对胰腺癌疫苗开发的了解做出重大贡献，并对人类胰腺癌的治疗产生直接影响。 公共卫生相关性：胰腺癌的发病率仍然与死亡率持平，迫切需要新的胰腺癌治疗方法。该项目旨在开发一种新型病毒样颗粒（VLP）刺激的树突状细胞（DC）免疫治疗胰腺癌疫苗。通过阻断DC中的免疫抑制因子，该疫苗可能增强处理肿瘤抗原的能力并产生肿瘤特异性反应偏向免疫，从而增强VLP免疫治疗针对胰腺癌的疗效。