Role of Obesity-Induced Immunosuppression in Pancreatic Cancer

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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.