Obesity affects immunity to kidney cancer

肥胖影响肾癌免疫力

• 批准号: 8610465
• 负责人: Lyse A Norian
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610465
• 关键词: Address; Affect; Biological Markers; CD8B1 gene; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cessation of life; Comorbidity; Data; Defect; Dendritic Cells; Diet; Distal; Effectiveness; Epidemiologic Studies; Failure; Future; Goals; Healthcare; Human; Immune; Immune response; Immunity; Immunologics; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammatory; Interleukin-1; Interleukin-17; Kidney; Kidney Neoplasms; Knowledge; Leukocytes; Life; Life Expectancy; Link; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Obese Mice; Obesity; Obesity associated cancer; Patients; Pattern; Phenotype; Population; Positioning Attribute; Prevalence; Primary Neoplasm; Process; Publications; Quality of life; Regulatory T-Lymphocyte; Renal carcinoma; Reporting; Risk; Serum; Site; Solid Neoplasm; Staging; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; TNF gene; Testing; Translational Research; Tumor Immunity; Work; adaptive immunity; base; cancer immunotherapy; cancer type; cytokine; exhaust; human subject; immune function; improved; macrophage; melanoma; mortality; pre-clinical; public health relevance; response; trafficking; tumor; tumor growth; tumorigenic

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.!

肥胖可以说是当今影响美国最重要的医疗危机。肥胖与一种 患上和死于几种癌症的风险增加，包括肾癌，但原因 死亡风险的增加目前尚不清楚。我们假设肥胖减少了正常的 免疫过程，使肿瘤生长受到控制，并降低癌症的有效性 免疫疗法先前的研究已经报道了肥胖者的抗肿瘤免疫力下降，但几乎没有发现。 机械数据来解释为什么会发生这种情况，并彻底了解肥胖对免疫系统的影响。 功能缺乏。我们已经开始通过探索肥胖和减少肥胖之间的联系来解决这一需求。 抗肿瘤免疫我们2012年的出版物是最早证明肥胖与肥胖相关的出版物之一。 免疫功能衰竭在这个应用中，我们的目标是定义细胞和分子基础 肥胖小鼠和人类抗肿瘤免疫力受损。目前，绝大多数临床前 癌症模型只使用瘦老鼠，所以他们没有解决肥胖或其他并发症对抗肿瘤的影响。 肿瘤免疫我们的长期目标是确定特异性免疫缺陷，这些缺陷是在对免疫缺陷的反应中产生的。 肥胖和肿瘤生长的结合，然后利用这些信息来开发有效的 癌症患者的免疫疗法。我们建议的理由是，通过了解 肥胖对抗肿瘤免疫的影响，我们将能够在未来优化免疫疗法。 研究，从而延长肾癌和其他肥胖患者的预期寿命和生活质量- 相关癌症，如黑色素瘤和前列腺癌。另外，我们的研究应该能揭示新的肥胖症- 相关免疫学模式，可作为免疫治疗失败患者的预测生物标志物， 肾癌和其他与肥胖有关的癌症。 总体假设：肥胖导致DC和基于T细胞的肾脏适应性免疫的可逆性缺陷 癌症，导致免疫失败和不受控制的肿瘤生长导致的死亡率升高。 目标1。确定肥胖诱导的肾癌小鼠T细胞启动和效应功能的改变。 目标2.定义肥胖诱导的肾癌小鼠免疫抑制细胞群的改变。 目标3.在患有肾肿瘤的肥胖人类受试者中确定肥胖相关的抗肿瘤免疫变化。 我们希望我们的研究结果能够大大推进对肥胖改变人类生活方式的基本理解。 抗肿瘤免疫，从而促进不受控制的肿瘤生长和肾癌和其他癌症的死亡率。 肥胖相关的癌症我们在这些研究过程中获得的知识将提供一个框架， 用于未来的转化研究，旨在提高肥胖和消瘦患者免疫治疗的有效性。 癌症患者！