Immunometabolic and epigenetic effects of obesity on innate immune surveillance in cancer

项目摘要 肥胖症在全球范围内已达到流行病的程度，并带来最大的健康和经济负担 是许多与肥胖相关的疾病。在这些疾病中，肥胖是一个很强的风险因素， 癌症，占某些癌症的49%。预计肥胖将很快取代 吸烟是导致癌症的主要可预防因素。尽管公众意识有所提高， 在实施预防战略的同时，肥胖症和相关疾病的流行仍在继续。因此存在 了解肥胖导致其他疾病的途径， 制定新的策略来阻止他们的发展。 现在认识到肥胖与免疫失调有关，这可能是导致肥胖的原因。 一些肥胖相关疾病。自然杀伤（NK）细胞是所谓的，由于其天然的 对肿瘤细胞的细胞毒性。我们之前已经证明肥胖者的NK细胞减少 细胞数量和剩余的NK细胞不能有效地杀死肿瘤细胞。关键 未回答的问题是1）肥胖如何诱导NK细胞缺陷，2）NK细胞损伤 增加肥胖者患癌症的风险，以及3）肥胖诱导的免疫功能障碍是否可以逆转或 防止。该项目将使用多学科方法来破译表观遗传和代谢 肥胖症患者NK细胞的变化导致其无法检测和杀死肿瘤。 免疫代谢正迅速成为一个具有巨大潜力的疾病治疗领域， 仍有待发现该项目的结果将使人们对复杂的变化有新的认识， 发生在肥胖症的先天免疫细胞中，以及它们如何影响免疫监视。它还将揭示一个 代谢途径和表观遗传修饰之间的大部分未探索的交叉点， 免疫系统我们的初步数据显示，肥胖的影响类似于雷帕霉素 治疗对抑制NK细胞功能的影响。这可能会影响 先天免疫系统在遇到外来或受损细胞时对其起作用， 至少部分解释了肥胖者感染和癌症风险的增加。

Project Summary Obesity has reached epidemic proportions globally with the biggest heath and economic burden being the many obesity-related diseases. Among these diseases, obesity is a strong risk factor for cancer, accounting for up to 49% of certain cancers. It is expected that obesity will soon replace smoking as the leading preventable cause of cancer. Despite increased public awareness and prevention strategies, the prevalence of obesity and related diseases continue. Therefore there is increased urgency to understand the pathways whereby obesity leads to other diseases, and to develop new strategies prevent their progression. It is now appreciated that obesity is associated with immune dysregulation, which may be the cause of some obesity related diseases. Natural killer (NK) cells are so-called due to their natural cytotoxicity against tumors cells. We have previously shown that obese individuals have reduced NK cell numbers and the remaining NK cells are unable to kill tumors cells efficiently. The key unanswered questions are 1) how does obesity induce NK cell defects, 2) Does NK cell impairment increase the risk of cancer in obesity, and 3) Can obesity induced immune dysfunction be reversed or prevented. This project will use a multi-disciplinary approach to decipher if epigenetic and metabolic changes in NK cells in obesity lead to their inability to survey and kill tumors. Immunometabolism is rapidly becoming an area of huge potential for treating disease, however much is still to be discovered. Results from this project will yield new insight into the complex changes that occur in innate immune cells in obesity and how they affect immune surveillance. It will also reveal a largely unexplored intersection between metabolic pathways and epigenetic modifications in the immune system. Our preliminary data shows that the effect of obesity is analogous to rapamycin treatment in terms of the effect on dampening NK cell functions. This likely impacts the ability of the innate immune system to act upon foreign or damaged cells when they encounter them, and may at least partly explain the increased risk of infection and cancer in obese individuals.