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。为了研究肥胖和胰腺癌风险之间关系的潜在机制，我们在胰腺癌的皮下（Panc.02）和自发转基因（LSL-KrasG 12 D/PDX-1-Cre/Ink 4alox/lox+/-）模型中使用饮食诱导的肥胖范例。将C57 BL/6或Kras/Ink 4a转基因小鼠置于30% kcal碳水化合物卡路里限制、10%或60 kcal%脂肪饮食上，随意喂食以分别产生瘦小鼠、对照小鼠和肥胖小鼠。我们的初步数据表明，肥胖显着促进肿瘤生长，并降低两种胰腺肿瘤模型的生存率，而瘦动物对肿瘤生长的保护最好。此外，我们已经表明，肥胖减少自然杀伤（NK）细胞的细胞毒性，在体外和体内抗原特异性CD 4 + T细胞增殖，抗原特异性CD 8 + T细胞的细胞毒性和干扰素-？在非荷瘤动物中产生。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受到损害，增加肥胖。另外，肥胖导致骨髓源性抑制细胞（MDSC）在携带胰腺肿瘤的小鼠的脾和肿瘤引流淋巴结中积累。MDSC是一种高度免疫抑制的细胞类型，常见于人类和肿瘤动物模型中。最后，我们观察到肥胖荷瘤动物血清中炎性细胞因子和前列腺素PGE 2的增加。因此，我们假设肥胖诱导的肿瘤发病率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恶化介导的，这两者都可能部分地由肥胖诱导的PGE 2增加介导。提出了三个具体的目标来研究1）肥胖诱导的免疫监视功能障碍的作用，2）肥胖诱导的免疫抑制因子的增加，和3）肥胖诱导的PGE 2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。该项目的成功完成可能会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，并防止肥胖诱导的促肿瘤发生环境的出现。

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.