Role of Obesity-Induced Immunosuppression in Pancreatic Cancer

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机制，我们在胰腺癌皮下（Panc.02）和自发转基因（LSL-KrasG12D/PDX-1-Cre/Ink4alox/lox+/-）模型中使用了饮食诱导的肥胖范式。C57BL/6或Kras/Ink4a转基因小鼠分别饲喂30%卡路里的碳水化合物限制卡路里，10%或60卡路里的脂肪随意喂养，分别产生瘦小鼠，对照组和肥胖小鼠。我们的初步数据表明，在两种胰腺肿瘤模型中，肥胖显著促进肿瘤生长并降低存活，而瘦肉动物对肿瘤生长具有最好的保护作用。此外，我们已经证明，肥胖可以降低自然杀伤细胞（NK）的细胞毒性、体内和体外抗原特异性CD4+ T细胞增殖、抗原特异性CD8+ T细胞毒性和干扰素-？非肿瘤动物的生产。在所有测量的结果中，肥胖和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会因肥胖增加而受损。此外，肥胖导致骨髓源性抑制细胞（MDSCs）在胰腺荷瘤小鼠的脾脏和肿瘤引流淋巴结中积累。MDSCs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。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，我们假设肥胖引起的肿瘤发病率的增加可能是由抗肿瘤免疫效应机制的损害和肿瘤源性免疫抑制因子的加剧介导的，这两者都可能部分由肥胖引起的PGE2的增加介导。我们提出了三个具体的研究目标：1)肥胖诱导的免疫损伤在免疫监视中的作用；2)肥胖诱导的免疫抑制因子的增加；3)肥胖诱导的PGE2的增加在介导这些导致胰腺肿瘤加速生长的免疫变化中的作用。这个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，这些策略可以在肿瘤发展的早期利用免疫系统的力量，防止肥胖诱导的促肿瘤环境的出现。

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.