Obesity Affects Immunity to Kidney Cancer

肥胖影响肾癌的免疫力

• 批准号: 9121679
• 负责人: Lyse A Norian
• 金额: $ 14.07万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/9121679
• 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; Health; 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; response; trafficking; tumor; tumor growth; tumorigenic

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.

描述（由申请人提供）：肥胖可以说是当今影响美国最重要的医疗危机。肥胖与包括肾癌在内的几种癌症的发病和死亡风险增加有关，但死亡风险增加的原因目前尚不清楚。我们假设肥胖减少了正常的免疫过程，控制肿瘤的生长，降低了癌症免疫治疗的有效性。先前的研究报道了肥胖患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，并且缺乏对肥胖对免疫功能影响的透彻理解。我们已经开始通过探索肥胖和抗肿瘤免疫减弱之间的联系来解决这一需求。我们2012年发表的论文是第一批证明肥胖与免疫治疗失败有关的论文之一。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鼠，因此它们没有解决肥胖或其他合并症对抗肿瘤免疫的影响。我们的长期目标是确定具体的