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.

项目总结

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

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

• DOI: 10.1038/s41590-018-0094-2
• 发表时间: 2018-05
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Kohlgruber AC;Gal-Oz ST;LaMarche NM;Shimazaki M;Duquette D;Koay HF;Nguyen HN;Mina AI;Paras T;Tavakkoli A;von Andrian U;Uldrich AP;Godfrey DI;Banks AS;Shay T;Brenner MB;Lynch L
• 通讯作者: Lynch L