Role of Obesity-Induced Immunosuppression in Pancreatic Cancer

肥胖引起的免疫抑制在胰腺癌中的作用

基本信息

批准号：
8640896
负责人：
Connie J Rogers
金额：
$ 7.23万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640896
关键词：
Adoptive Transfer Adult Affect Animal Model Animals Antibodies Antigen Presentation Antigens Biological Biological Models Breast C57BL/6 Mouse CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Caloric Restriction Cancer Model Carbohydrates Cause of Death Cells Characteristics Colon Data Development Diet Dinoprostone Disease Progression Environment Fatty acid glycerol esters Future Health Human Immune Immune system Immunologic Monitoring Immunosuppression Immunosuppressive Agents Impairment In Vitro Incidence Inflammatory Integration Host Factors Interferons Interleukin-1 Knockout Mice Lymphoid Tissue Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mus Myelogenous Natural Killer Cells Obese Mice Obesity Obesity associated cancer Outcome Measure Overweight PTGS2 gene Pancreas Population Prevention Prevention strategy Production Prostaglandins Public Health Regimen Regulation Risk Risk Factors Role Serum Signal Transduction Site Spleen Suppressor-Effector T-Lymphocytes T-Cell Proliferation T-Lymphocyte Testing Therapeutic Transgenic Mice Transgenic Organisms Tumor Immunity Tumor-Derived base cancer prevention cancer risk celecoxib cell type cytokine cytotoxicity design feeding immune function in vivo insight knowledge base lymph nodes novel pancreatic neoplasm prevent public health relevance research study subcutaneous tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Obesity is associated with an increased risk and reduced survival from many forms of cancer. In an effort to study the mechanisms underlying the relationship between obesity and pancreatic cancer risk, we used a diet-induced obesity paradigm in both a subcutaneous (Panc.02) and a spontaneous transgenic (LSL-KrasG12D/PDX-1-Cre/Ink4alox/lox+/- ) model of pancreatic cancer. C57BL/6 or Kras/Ink4a transgenic mice were placed on either a 30% kcal carbohydrate calorie restricted, a 10% or a 60 kcal% fat diet fed ad libitum to generate lean, control and obese mice, respectively. Our preliminary data demonstrate that obesity significantly enhances tumor growth and decreases survival in both pancreatic tumor models while lean animals have the best protection from tumor growth. Additionally, we have shown that obesity reduces natural killer (NK) cell cytotoxicity, in vitro and in vivo antigen-specific CD4+ T cell proliferation, and antigen- specific CD8+ T cell cytotoxicity and interferon-? production in non-tumor bearing animals. In all outcomes measured, there was an inverse relationship between adiposity and immune function. These data suggest that many immunosurveillance mechanisms may be impaired by increasing obesity. Additionally, obesity results in the accumulation of myeloid derived suppressor cells (MDSCs) in the spleen and tumor draining lymph nodes of pancreatic tumor-bearing mice. MDSCs are a highly immunosuppressive cell type commonly seen in humans and animal models with tumors. Lastly, we observed an increase in inflammatory cytokines and the prostaglandin, PGE2 in the sera of obese tumor-bearing animals. Therefore, we hypothesize that the obesity-induced increase in tumor incidence may be mediated by an impairment of anti- tumor immune effector mechanisms and an exacerbation of tumor-derived immunosuppressive factors which both may be mediated in part, by an obesity-induced increase in PGE2. Three specific aims are proposed to study 1) the role of obesity-induced impairments in immunosurveillance 2) obesity-induced increase in immunosuppressive factors, and 3) the role of an obesity-induced increase in PGE2 in mediating these immunological changes that result in accelerated pancreatic tumor growth. Successful completion of this project may provide critical insight into the development of more effective cancer prevention strategies that harness the power of the immune system early in tumor development and prevent the emergence of an obesity-induced pro-tumorigenic environment.

描述（由申请人提供）：肥胖与多种癌症的风险增加和生存率降低有关。为了研究肥胖与胰腺癌风险之间关系的潜在机制，我们在皮下注射 (Panc.02) 和自发转基因 (LSL-KrasG12D/PDX-1-Cre/Ink4alox) 中使用了饮食诱导的肥胖范例。 /lox+/- ) 胰腺癌模型。 C57BL/6 或 Kras/Ink4a 转基因小鼠被置于 30% kcal 碳水化合物热量限制、10% 或 60 kcal% 脂肪饮食中随意喂养，分别产生瘦小鼠、对照小鼠和肥胖小鼠。我们的初步数据表明，在两种胰腺肿瘤模型中，肥胖显着促进肿瘤生长并降低存活率，而瘦动物对肿瘤生长具有最佳保护。此外，我们还发现肥胖会降低自然杀伤 (NK) 细胞的细胞毒性、体外和体内抗原特异性 CD4+ T 细胞增殖、抗原特异性 CD8+ T 细胞的细胞毒性和干扰素-α。在非荷瘤动物中生产。在所有测量的结果中，肥胖与免疫功能之间存在反比关系。这些数据表明，许多免疫监视机制可能因肥胖的增加而受到损害。此外，肥胖会导致胰腺肿瘤小鼠的脾脏和肿瘤引流淋巴结中骨髓源性抑制细胞（MDSC）的积累。 MDSC 是一种高度免疫抑制的细胞类型，常见于人类和动物肿瘤模型中。最后，我们观察到肥胖荷瘤动物血清中炎症细胞因子和前列腺素 PGE2 的增加。因此，我们推测，肥胖引起的肿瘤发病率增加可能是由抗肿瘤免疫效应机制受损和肿瘤源性免疫抑制因子加剧介导的，而这两者都可能部分是由肥胖引起的肿瘤发病率增加介导的。前列腺素E2。提出了三个具体目标来研究 1) 肥胖引起的免疫监视损伤的作用 2) 肥胖引起的免疫抑制因子增加，以及 3) 肥胖引起的 PGE2 增加在介导这些免疫变化中的作用，这些变化导致加速胰腺肿瘤生长。该项目的成功完成可能为开发更有效的癌症预防策略提供重要的见解，这些策略在肿瘤发展的早期利用免疫系统的力量并防止肥胖诱导的促肿瘤发生环境的出现。