Obesity increased cancer risk by NKT cell depletion (PQ1)

描述（由申请人提供）：肥胖症的流行威胁着代谢紊乱和包括癌症在内的其他疾病的大量激增。现在已知炎症可以加重肥胖和相关的代谢综合征。这会导致慢性炎症，与其他因素一起导致癌症风险。逆转肥胖或代谢综合征会使癌症风险降至正常水平。自然杀伤T细胞（NKT）是保守的先天性样细胞， 可以积极或消极地影响免疫细胞，从而影响各种模型中的反应和结果。我们已经在癌症模型中和体外用人NKT逆转了功能性NKT缺陷。NKT是保护性的，但在肥胖症中也可逆地消耗。拟议的研究将确定NKT在代谢中的新作用的机制，并确定其治疗代谢综合征的治疗潜力，以及肥胖症癌症风险增加的影响。假设：在肥胖症中，我们假设保护性抗肿瘤NKT细胞在整个身体中耗尽，导致巨噬细胞失去控制，从而导致代谢疾病综合征和癌症增加。这一假设导致了以下可检验且不相互排斥的预测：a）由肥胖引起的内质网应激导致质膜上CD 1d的损失，因此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，即如何逆转肥胖症的这些缺陷，我们也将讨论。目的1：确定癌症风险和侵袭性是否与肥胖症中iNKT损失相关。目的2：确定逆转NKT细胞缺陷是否可以在肥胖相关癌症中起到保护作用。为了进行这些研究，我们将利用2种癌症模型，其中我们已经鉴定了iNKT缺陷，并通过高脂肪饮食将这些与肥胖结合联合收割机以测试增加的攻击性。然后，我们将确定逆转这些缺陷的最佳方法，并测量肥胖、代谢综合征和癌症的改善情况。我们正在免疫监测黑色素瘤中iNKT重建的试验，因此有将我们的发现转化为临床的经验。 公共卫生相关性：肥胖增加代谢紊乱，包括癌症和炎症在内的炎性疾病可加重肥胖、癌症和相关的代谢综合征。自然杀伤T细胞（“NKT”）识别与CD 1分子结合的脂质，我们发现CD 1和NKT在肝脏和脂肪中富集，在癌症和肥胖中耗尽，但在体重减轻后和通过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。

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.