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

肥胖对癌症先天免疫监视的免疫代谢和表观遗传影响

• 批准号: 10459275
• 负责人: Lydia Lynch
• 金额: $ 40.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459275
• 关键词: Accounting; Adult; Affect; Area; Awareness; Cardiovascular Diseases; Cell Count; Cell physiology; Cells; Complex; Data; Defect; Development; Disease; Economic Burden; Epidemic; Epigenetic Process; Healthcare Systems; Human; Immune; Immune System Diseases; Immune system; Immunologic Surveillance; Impairment; In Vitro; Infection; Innate Immune System; Lead; Malignant Neoplasms; Metabolic; Metabolic Pathway; Modification; Natural Killer Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Overweight; Pathway interactions; Persons; Population; Prevalence; Preventable cancer cause; Prevention strategy; Proteins; RNA; Risk Factors; Sirolimus; Smoking; Surveys; cancer cell; cancer risk; cell injury; cytotoxicity; design; diet-induced obesity; frontier; functional restoration; health economics; in vivo; infection risk; insight; interdisciplinary approach; mouse model; neoplastic cell; obese patients; obese person; prevent; tumor; tumor progression

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.

项目摘要 肥胖在全球范围内达到了流行病，最大的荒地和经济负担 是许多与肥胖有关的疾病。在这些疾病中，肥胖是强大的风险因素 癌症，占某些癌症的49％。预计肥胖很快就会取代 吸烟是癌症的主要预防原因。尽管公众意识提高了，并且 预防策略，肥胖和相关疾病的流行率仍在继续。因此有 加剧了了解肥胖导致其他疾病的途径的紧迫性 制定新策略阻止其发展。 现在，人们对肥胖症与免疫失调有关，这可能是原因 一些与肥胖有关的疾病。天然杀手（NK）细胞由于天然而被称为 针对肿瘤细胞的细胞毒性。我们以前已经表明肥胖个体减少了NK 细胞数和其余NK细胞无法有效杀死肿瘤细胞。钥匙 未解决的问题是1）肥胖如何诱导NK细胞缺陷，2）NK细胞损伤会 增加肥胖症中癌症的风险，3）肥胖会诱发免疫功能障碍或 阻止。该项目将使用多学科的方法来解密，如果表观遗传和代谢 肥胖症中NK细胞的变化导致它们无法进行调查和杀死肿瘤。 免疫代谢迅速成为治疗疾病潜力巨大的领域，但是 仍有要发现。该项目的结果将使人们对复杂变化的新见解 发生在肥胖症中的先天免疫细胞中，以及它们如何影响免疫监测。它也会揭示 代谢途径与表观遗传修饰之间的相交在很大程度上未开发 免疫系统。我们的初步数据表明，肥胖的作用类似于雷帕霉素 根据对衰减NK细胞功能的影响的治疗。这可能会影响 先天免疫系统遇到外国或受损的细胞，并可能在 至少部分解释了肥胖个体感染和癌症的风险增加。

项目成果

Diet, nutrient supply, and tumor immune responses.

• DOI: 10.1016/j.trecan.2023.06.003
• 发表时间: 2023-07
• 期刊: Trends in cancer
• 影响因子: 18.4
• 作者: C. McIntyre;Ayantu Temesgen;L. Lynch

Immune and non-immune functions of adipose tissue leukocytes.

脂肪组织白细胞的免疫和非免疫功能。

• DOI: 10.1038/s41577-021-00635-7
• 发表时间: 2022
• 期刊: Nature reviews. Immunology
• 作者: Trim,WV;Lynch,L
• 通讯作者: Lynch,L

γδ T cells unveil invisible tumors.

γT 细胞揭示了看不见的肿瘤。

• DOI: 10.1016/j.it.2023.01.011
• 发表时间: 2023
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Koay,Hui-Fern;Lynch,Lydia
• 通讯作者: Lynch,Lydia

Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function.

• DOI: 10.1084/jem.20210042
• 发表时间: 2022-03-07
• 期刊: The Journal of experimental medicine
• 作者: Dyck L;Prendeville H;Raverdeau M;Wilk MM;Loftus RM;Douglas A;McCormack J;Moran B;Wilkinson M;Mills EL;Doughty M;Fabre A;Heneghan H;LeRoux C;Hogan A;Chouchani ET;O'Shea D;Brennan D;Lynch L
• 通讯作者: Lynch L

Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.

二甲双胍和喂养会增加人类抑制食欲的代谢物 Lac-Phe 的水平。

• DOI: 10.1038/s42255-024-01018-7
• 发表时间: 2024
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Scott,Barry;Day,EmilyA;O'Brien,KatieL;Scanlan,John;Cromwell,Grace;Scannail,AineNi;McDonnell,MarieE;Finlay,DavidK;Lynch,Lydia
• 通讯作者: Lynch,Lydia