Obesity increased cancer risk by NKT cell depletion (PQ1)

肥胖会因 NKT 细胞耗竭而增加癌症风险 (PQ1)

• 批准号: 8374250
• 负责人: MARK A EXLEY
• 金额: $ 22.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374250
• 关键词: Accounting; Address; Adipocytes; Adipose tissue; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Autologous; Back; Body Weight decreased; Body fat; CD1 Antigens; Caloric Restriction; Cancer Center; Cancer Model; Cardiovascular Diseases; Cell membrane; Cells; Chronic; Clinic; Data; Defect; Dendritic Cells; Diet; Disease; Disease model; Epidemic; Equilibrium; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Galactosylceramides; Glycolipids; Human; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Interleukin-12; Leptin; Lipid Binding; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Metformin; Modeling; Monitor; Morbidity - disease rate; Mus; Myelogenous; Neoplasm Metastasis; Obese Mice; Obesity; Obesity associated cancer; Outcome; Pathology; Patients; Phase I Clinical Trials; Physiological; Population; Production; Protocols documentation; Publishing; Relative (related person); Reporting; Role; Running; Serum; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Translating; Triglycerides; Weight Gain; Work; bariatric surgery; base; cancer risk; cytokine; cytotoxicity; endoplasmic reticulum stress; experience; improved; in vivo; insulin sensitivity; killer T cell; macrophage; melanoma; monocyte; mortality; novel; outcome forecast; preclinical study; reconstitution; response; tumor; tumor growth

DESCRIPTION (provided by applicant): The obesity epidemic threatens a massive surge in metabolic disorders and other diseases including cancer. It is now known that inflammation can reinforce obesity and associated metabolic syndrome. This leads to chronic inflammation, which with other factors contribute to cancer risk. Reversing obesity or metabolic syndrome brings cancer risk toward normal levels. Natural Killer T cells (NKT) are conserved innate-like cells that can positively or negatively influence immune cells and therefore responses and outcomes in various models. We have reversed functional NKT defects in a cancer model and in vitro with human NKT. NKT are protective, but also reversibly depleted in obesity. The proposed studies will determine the mechanism for a novel role of NKT in metabolism and determine their therapeutic potential for treatment of metabolic syndrome, with implications for increased risk of cancer in obesity. Hypothesis: In obesity, we hypothesize that protective anti-tumor NKT cells are depleted throughout the body, contributing to loss of control of macrophages and consequent metabolic disease syndrome and increased cancer. This hypothesis leads to the following testable and not mutually exclusive predictions: a) Endoplasmic reticulum stress caused by obesity, leads to a loss of CD1d on the plasma membrane and therefore a decline in iNKT cells, and / or b) cancers that escape physiological control have suppressed iNKT, and this is more aggressive in obesity. Finally, there is the therapeutic question of how to reverse such defects in obesity, which we will also address. Aim 1: Determine whether cancer risk and aggressiveness are associated with iNKT loss in obesity. Aim 2: Determine whether reversing NKT cell defects can be protective in obesity-associated cancer. To perform these studies, we will exploit 2 models of cancer in which we have identified iNKT defects and combine these with obesity through high fat diets to test for increased aggressiveness. We will then determine optimal ways to reverse these defects and measure improvements in obesity, metabolic syndrome, and cancer. We are immuno-monitoring a trial of iNKT reconstitution in melanoma, so have experience in translating our findings to the clinic. PUBLIC HEALTH RELEVANCE: Obesity increases metabolic disorders and inflammatory diseases including cancer and inflammation can reinforce obesity, cancer, and associated metabolic syndrome. Natural Killer T cells ('NKT') recognize lipids bound to the CD1 molecule and we found that CD1 and NKT are enriched in liver and fat, depleted in cancer and obesity, but restored following weight loss and by NKT-targeted approaches. We will determine whether NKT dysfunction is exacerbated in obese cancer and their therapeutic potential.

描述（由申请人提供）：肥胖流行威胁着代谢紊乱和包括癌症在内的其他疾病的大幅增加。现在已知炎症会加剧肥胖和相关的代谢综合征。这会导致慢性炎症，而慢性炎症与其他因素一起会增加癌症风险。逆转肥胖或代谢综合征可使癌症风险降至正常水平。自然杀伤 T 细胞 (NKT) 是保守的先天样细胞， 可以对免疫细胞产生积极或消极的影响，从而影响各种模型中的反应和结果。我们已经在癌症模型和体外使用人类 NKT 逆转了功能性 NKT 缺陷。 NKT 具有保护作用，但在肥胖时也会可逆地减少。拟议的研究将确定 NKT 在代谢中的新作用机制，并确定其治疗代谢综合征的潜力，这对肥胖患者患癌症的风险增加具有影响。假设：在肥胖症中，我们假设全身保护性抗肿瘤 NKT 细胞被耗尽，导致巨噬细胞失去控制，进而导致代谢性疾病综合征和癌症增加。这一假设导致以下可检验且不相互排斥的预测：a) 肥胖引起的内质网应激，导致质膜上 CD1d 的丢失，从而导致 iNKT 细胞减少，和/或 b) 逃避生理控制的癌症抑制了 iNKT，这在肥胖中更具侵袭性。最后，还有一个治疗问题，即如何扭转肥胖的此类缺陷，我们也将解决这个问题。目标 1：确定癌症风险和侵袭性是否与肥胖患者 iNKT 缺失相关。目标 2：确定逆转 NKT 细胞缺陷是否可以对肥胖相关癌症起到保护作用。为了进行这些研究，我们将利用两种癌症模型，在这些模型中我们已经确定了 iNKT 缺陷，并通过高脂肪饮食将其与肥胖相结合，以测试攻击性的增加。然后，我们将确定扭转这些缺陷的最佳方法，并衡量肥胖、代谢综合征和癌症的改善情况。我们正在对黑色素瘤中的 iNKT 重建试验进行免疫监测，因此拥有将我们的发现转化为临床的经验。 公共卫生相关性：肥胖会增加代谢紊乱和炎症性疾病，包括癌症，而炎症会加剧肥胖、癌症和相关代谢综合征。自然杀伤 T 细胞 (“NKT”) 识别与 CD1 分子结合的脂质，我们发现 CD1 和 NKT 在肝脏和脂肪中丰富，在癌症和肥胖症中减少，但在减肥后通过 NKT 靶向方法恢复。我们将确定 NKT 功能障碍是否在肥胖癌症中加剧及其治疗潜力。