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

• 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
• 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

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）：肥胖与许多形式的癌症的风险增加和降低的生存有关。为了研究肥胖与胰腺癌风险之间关系的基础机制，我们在皮下（Panc.02）和自发转基因（LSL-KRASG12D/PDX-1-CRE/PDX-1-CRE/INK4ALOX/LOX/LOX/LOX/LOX +/- parcric cancer s os pcancric cancer and Parcreatic cancer cancer cancer cancer cancer cancer cancer cancer cance将C57BL/6或KRAS/INK4A转基因小鼠放置在限制的30％kcal碳水化合物卡路里，10％或60 kcal％脂肪饮食中分别产生额外的饮食，分别产生瘦肉，控制和肥胖小鼠。我们的初步数据表明，肥胖可显着增强肿瘤的生长并降低两种胰腺肿瘤模型的生存率，而瘦动物对肿瘤生长具有最好的保护。此外，我们已经表明肥胖可以减少天然杀伤（NK）细胞毒性，体外和体内抗原特异性CD4+ T细胞增殖，以及抗原 - 特异性CD8+ T细胞细胞毒性和Interferon-？在非肿瘤轴承动物中产生。在测得的所有结果中，肥胖和免疫功能之间存在反比关系。这些数据表明，增加肥胖症可能会损害许多免疫监视机制。此外，肥胖会导致髓样衍生的抑制细胞（MDSC）在胰腺肿瘤小鼠的脾脏和肿瘤排干淋巴结中的积累。 MDSC是在人类和具有肿瘤的动物模型中通常看到的高度免疫抑制细胞类型。最后，我们观察到炎性细胞因子和前列腺素的增加，肥胖肿瘤动物血清中的PGE2。因此，我们假设肥胖诱导的肿瘤发病率的增加可能是通过抗肿瘤免疫效应机制的损害介导的，并且肿瘤衍生的免疫抑制因子加剧了，这两者都可以由肥胖诱导的PGE2增加。提出了三个具体目的来研究1）肥胖诱导的损伤在免疫监护率中的作用2）肥胖诱导的免疫抑制因素的增加，以及3）肥胖诱导的PGE2在介导这些免疫学变化的PGE2增加的作用，从而导致加速的pancreatic tumor生长。该项目的成功完成可能会为制定更有效的预防癌症预防策略提供批判性的见解，这些策略在肿瘤发育早期利用免疫系统的力量，并防止肥胖引起的亲苏莫尔菌环境的出现。