Obesity Affects Immunity to Kidney Cancer

描述(申请人提供)：肥胖症可以说是当今影响美国最重要的医疗危机。肥胖与患多种癌症和死于多种癌症的风险增加有关，包括肾癌，但死亡风险增加的原因目前尚不清楚。我们假设肥胖会降低控制肿瘤生长的正常免疫过程，并降低癌症免疫治疗的有效性。以前的研究已经报道了肥胖者抗肿瘤免疫功能下降，但几乎没有机制数据来解释为什么会发生这种情况，而且缺乏对肥胖对免疫功能影响的透彻了解。我们已经开始通过探索肥胖和抗肿瘤免疫力下降之间的联系来解决这一需求。我们2012年的出版物是第一批证明肥胖与免疫治疗失败有关的出版物之一。在这项应用中，我们的目标是确定肥胖小鼠和人类抗肿瘤免疫受损的细胞和分子基础。目前，绝大多数临床前癌症模型只使用瘦小的小鼠，因此它们没有解决肥胖或其他共病对抗肿瘤免疫的影响。我们的长期目标是确定具体的 在肥胖和肿瘤生长的共同作用下产生的免疫缺陷，然后利用这些信息为癌症患者开发有效的免疫疗法。我们建议的理由是，通过了解肥胖对抗肿瘤免疫的影响，我们将能够在未来的研究中优化免疫疗法，从而延长肾癌和其他肥胖相关癌症患者的预期寿命和生活质量，如黑色素瘤和前列腺癌。此外，我们的研究应该揭示新的肥胖相关免疫模式，这些模式可以作为肾癌和其他肥胖相关癌症患者免疫治疗失败的预测生物标志物。总体假设：肥胖导致基于DC和T细胞的肾癌适应性免疫的可逆缺陷，导致免疫治疗失败，并因肿瘤生长失控而增加死亡率。目的1.明确肥胖对肾癌小鼠T细胞启动和效应功能的影响。目的2.明确肥胖对肾癌小鼠免疫抑制细胞群的影响。目的3.研究肥胖肾肿瘤受试者抗肿瘤免疫功能与肥胖相关的变化。我们预计我们的发现将大大促进对肥胖改变抗肿瘤免疫的方式的基本理解，从而促进肿瘤的不受控制的生长和肾癌和其他肥胖相关癌症的死亡率。我们在这些研究过程中获得的知识将为未来旨在改善肥胖症和瘦癌症患者免疫疗法有效性的转化研究提供一个框架。

DESCRIPTION (provided by applicant): Obesity is arguably the most important healthcare crisis affecting the US today. Obesity is associated with an increased risk for developing and dying from several types of cancer, including kidney cancer, but the causes of this heightened risk of death are currently unclear. We hypothesize that obesity diminishes the normal immunological processes that keep tumor growth in check and decreases the effectiveness of cancer immunotherapies. Prior studies have reported decreased anti-tumor immunity in the obese, but there is little mechanistic data to explain why this occurs, and a thorough understanding of the impact of obesity on immune function is lacking. We have begun to address this need by exploring the link between obesity and diminished anti-tumor immunity. Our 2012 publication was one of the first to demonstrate that obesity is associated with immunotherapeutic failure. In this application, our objective is to define the cellular and molecular basis for impaired anti-tumor immunity in obese mice and humans. Currently, the vast majority of pre-clinical cancer models use only lean mice, so they do not address the impact of obesity or other co-morbidities on anti- tumor immunity. Our long-term goal is to identify specific immunological defects that arise in response to the combination of obesity and tumor outgrowth, then leverage this information to develop effective immunotherapies for cancer patients. The rationale for our proposal is that by understanding the consequences of obesity on anti-tumor immunity, we will be able to optimize immunotherapies in future studies, thereby prolonging life expectancy and quality of life for patients with kidney cancer and other obesity- related cancers, such as melanoma and prostate cancer. In addition, our studies should reveal new obesity- related immunologic patterns that can act as predictive biomarkers for immunotherapy failure in patients with kidney cancer and other obesity-related cancers. Overall Hypothesis: Obesity causes reversible defects in DC and T cell-based adaptive immunity to kidney cancer, resulting in immunotherapeutic failure and heightened mortality from uncontrolled tumor growth. Aim 1. Identify obesity-induced alterations in T cell priming and effector function in mice with kidney cancer. Aim 2. Define obesity-induced alterations in immunosuppressive cell populations in mice with kidney cancer. Aim 3. Identify obesity-related changes in anti-tumor immunity in obese human subjects with renal tumors. We expect our findings to substantially advance fundamental understanding of the ways in which obesity alters anti-tumor immunity, thereby promoting uncontrolled tumor growth and mortality from kidney cancer and other obesity-related cancers. The knowledge we gain during the course of these studies will provide a framework for future translational research aimed at improving the effectiveness of immunotherapies in obese and lean cancer patients.