CD40 Pathway in Pancreatic Adenocarcinoma

胰腺癌中的 CD40 通路

• 批准号: 8699019
• 负责人: Gregory L Beatty
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699019
• 关键词: Academic Medical Centers; Agonist; Antigen-Presenting Cells; B-Lymphocytes; Biometry; CD40 Antigens; Cancer Control; Cell Communication; Cells; Clinical; Clinical Research; Clinical Trials Design; Cytokine Signaling; Cytotoxic Chemotherapy; Data; Disease; Effectiveness; Genetically Engineered Mouse; Goals; Grant; Hematology; Human; Immune response; Immunity; Immunologic Monitoring; Immunologic Surveillance; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-10; Interleukin-6; Ionizing radiation; Laboratories; Leukocytes; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Modeling; Molecular; Monoclonal Antibodies; Mus; Natural Immunity; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phase; Physicians; Play; Pre-Clinical Model; Recruitment Activity; Research; Resistance; Role; Scientist; Shapes; Signal Pathway; T cell response; T-Lymphocyte; TNF gene; TNFRSF5 gene; Testing; Therapeutic; Training; Tumor Immunity; Work; career; chemotherapy; cytokine; gemcitabine; granulocyte; human disease; immune activation; improved; in vivo; lymph nodes; macrophage; mouse model; novel; novel therapeutics; oncology; response; skills; treatment strategy; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): This proposal investigates the CD40 pathway as a key regulator of immune surveillance in a genetically engineered mouse (GEM) model of pancreatic ductal adenocarcinoma (PDA). The candidate is a physician-scientist with training in immunology, hematology, and oncology who is proposing a 5 year mentored research plan with Drs. Carl June and Robert Vonderheide. Formal course work in biostatistics and clinical trial design and interpretation will advance the candidate's skills in interpreting the translational potential of findings obtained in preclinical models. The goal of this career plan is to establish an independent laboratory in an academic department of a university medical center. Research will focus on investigating mechanisms that regulate the capacity of CD40 activation to coordinate productive innate and adaptive anti-tumor immunity. This proposal will use a GEM model of PDA that recapitulates the salient features of human disease. Preliminary data demonstrate that systemic activation of the CD40 pathway can induce tumor regression in pancreatic cancer in mice and humans through a mechanism that is dependent on macrophages but not T cells or chemotherapy. CD40 activated macrophages actively infiltrate the tumor microenvironment, become tumoricidal, and deplete tumor stroma. The recruitment of T cells to the tumor microenvironment is shown to be restrained by IL-10 and the B7-CTLA-4 inhibitory signaling pathway. It is the central hypothesis of this proposal that CD40 plays a critical role in regulating immune surveillance in pancreatic ductal adenocarcinoma through activation of innate immunity but its ability to coordinate productive adaptive anti-tumor immunity is restrained by immunoregulatory pathways controlled by cancer inflammation. To test this hypothesis, three specific aims are proposed. AIM ONE will evaluate the role of leukocytes within the tumor microenvironment in regulating the capacity of CD40- activated macrophages to modulate the tumor microenvironment and induce tumor regression. AIM TWO will examine the role of cytokines in regulating CD40-induced anti-tumor activity. AIM THREE will investigate how cross-talk between antigen presenting cells and T cells regulates the ability of CD40 activation to recruit T cell specific immunity. RELEVANCE: Pancreatic cancer is a devastating disease with few therapeutic options. This proposal will use a mouse model that is indistinguishable from human PDA. Studies in this model will improve the understanding of pathways regulating immune activation within the tumor microenvironment of PDA and may identify novel therapeutic strategies for the treatment of PDA.

描述（由申请人提供）：本提案研究了 CD40 通路作为胰腺导管腺癌 (PDA) 基因工程小鼠 (GEM) 模型中免疫监视的关键调节因子。该候选人是一位接受过免疫学、血液学和肿瘤学培训的医师科学家，他提出了一项与 Drs. 一起进行为期 5 年的指导研究计划。卡尔·琼和罗伯特·冯德海德。生物统计学以及临床试验设计和解释方面的正式课程将提高考生解释临床前模型中获得的研究结果的转化潜力的技能。这个职业规划的目标是在一所大学医学中心的学术部门建立一个独立的实验室。研究将重点研究调节 CD40 激活能力的机制，以协调生产性先天性和适应性抗肿瘤免疫。该提案将使用 PDA 的 GEM 模型来概括人类疾病的显着特征。初步数据表明，CD40 通路的全身激活可以通过依赖于巨噬细胞而非 T 细胞或化疗的机制，诱导小鼠和人类胰腺癌的肿瘤消退。 CD40 激活的巨噬细胞主动渗透肿瘤微环境，具有杀肿瘤作用，并消耗肿瘤基质。 T 细胞向肿瘤微环境的募集被证明受到 IL-10 和 B7-CTLA-4 抑制信号通路的抑制。该提议的核心假设是，CD40 通过激活先天免疫在调节胰腺导管腺癌的免疫监视中发挥关键作用，但其协调生产性适应性抗肿瘤免疫的能力受到癌症炎症控制的免疫调节途径的限制。为了检验这一假设，提出了三个具体目标。 AIM ONE 将评估肿瘤微环境中白细胞在调节 CD40 激活巨噬细胞调节肿瘤微环境和诱导肿瘤消退的能力方面的作用。目标二将检查细胞因子在调节 CD40 诱导的抗肿瘤活性中的作用。目标三将研究抗原呈递细胞和 T 细胞之间的串扰如何调节 CD40 激活以招募 T 细胞特异性免疫的能力。相关性：胰腺癌是一种毁灭性的疾病，治疗选择很少。该提案将使用与人类 PDA 没有区别的小鼠模型。该模型的研究将增进对 PDA 肿瘤微环境内调节免疫激活途径的理解，并可能确定治疗 PDA 的新治疗策略。