Obesity increased cancer risk by NKT cell depletion (PQ1)

描述(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规模激增。现在已经知道，炎症会加剧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接近正常水平。自然杀伤T细胞(NKT)是一种保守的先天类细胞， 可以积极或消极地影响免疫细胞，从而在不同的模型中做出反应和结果。我们已经在癌症模型和体外用人NKT逆转了功能性NKT缺陷。NKT具有保护性，但在肥胖方面也会可逆地耗尽。拟议中的研究将确定NKT在新陈代谢中扮演新角色的机制，并确定它们治疗代谢综合征的潜力，这意味着肥胖中癌症风险的增加。假设：在肥胖中，我们假设保护性的抗肿瘤NKT细胞在全身耗尽，导致巨噬细胞失去控制，从而导致代谢性疾病综合征和癌症增加。这一假说导致了以下可测试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细胞的下降，和/或b)逃脱生理控制的癌症抑制了iNKT，这在肥胖症中更具侵略性。最后，还有一个治疗问题，即如何扭转肥胖症的这些缺陷，我们也将解决这个问题。目的1：确定癌症风险和侵袭性是否与肥胖患者iNKT丢失有关。目的2：确定逆转NKT细胞缺陷是否对肥胖相关癌症具有保护作用。为了进行这些研究，我们将利用两种癌症模型，在这两种模型中，我们已经确定了iNKT缺陷，并通过高脂肪饮食将它们与肥胖结合起来，以测试侵袭性的增加。然后，我们将确定逆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的iNKT重建试验进行免疫监测，因此有将我们的发现转化为临床的经验。 公共卫生相关性：肥胖会增加代谢紊乱，包括癌症和炎症在内的炎症性疾病会加剧肥胖、癌症和相关的代谢综合征。自然杀伤T细胞(‘NKT’)识别与CD1分子结合的脂类，我们发现CD1和NKT富含肝脏和脂肪，在癌症和肥胖症中缺失，但在减肥和NKT靶向治疗后恢复。我们将确定NKT功能障碍在肥胖癌症中是否加剧，以及它们的治疗潜力。

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.