Innate Immune Mechanisms Contributing to Cancer Growth in Obesity

肥胖导致癌症生长的先天免疫机制

• 批准号: 10278250
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 52.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278250
• 关键词: Acidity; Acids; Adult; Affect; Automobile Driving; Biological Assay; Blocking Antibodies; Blood donor; CTLA4 gene; Cancer Etiology; Cell physiology; Cells; Colon Carcinoma; Colorectal Cancer; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diet; Disease; Exhibits; Flow Cytometry; Frequencies; Genus Hippocampus; Growth; High Fat Diet; Human; Immune; Immune response; Impairment; Inflammatory Response; KRASG12D; Lipids; MC38; Malignant Neoplasms; Mediator of activation protein; Modeling; Mus; Non obese; Obese Mice; Obesity; Oleic Acids; Outcome; Overweight; Patients; Play; Population; Predisposition; Primary carcinoma of the liver cells; Production; Prognosis; Risk; Role; Sampling; Signal Transduction; Societies; Solid Neoplasm; TNF gene; Testing; Therapeutic Effect; Triglycerides; Tumor Immunity; Tumor-associated macrophages; United States; anti-PD-1/PD-L1; base; cancer therapy; cell type; colon cancer patients; colon growth; cytokine; diet-induced obesity; dietary; fatty acid oxidation; human data; immune checkpoint blockade; innate immune mechanisms; macrophage; melanoma; mortality; mouse model; neoplasm immunotherapy; neoplastic cell; novel; obese patients; obesogenic; overexpression; rapid growth; receptor; response; subcutaneous; therapy outcome; tumor; tumor growth; tumor metabolism; tumor microenvironment

Project Summary/Abstract Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, and obesity, which affects 40% of the population, not only increases the risk of developing CRC, but also increases CRC mortality through unknown mechanisms. Our preliminary studies demonstrate that CRC grows faster in mice rendered obese through a high fat diet (HFD), and that the tumor associated macrophages (TAMs) in these mice exhibit higher expression of the acid sensing receptor, GPR65, which is known to dampen the immune response. Moreover, in HFD-induced obese mice lacking GRP65, TAMs secrete more TNF-α and tumor growth is retarded. Given that TAMs but not normal tissue macrophages of obese mice exhibit increased GPR65, we examined the pH of the tumors in these mice and found them to be more acidic. On the basis of these findings, we hypothesize that excess lipids in the HFD alter tumor cell metabolism resulting in increased acid production, which potentiates GPR65 expression and signaling in TAMs, causing them to become immunosuppressive and promote tumor growth. To test this hypothesis we will pursue the following specific aims: 1) Determine the contribution of GPR65 signaling to TAM function and CRC growth under conditions of obesity by determining if the cAMP- PKA signaling axis, which functions downstream of GPR65, is activated in TAMs of obese mice and controls TNF-α production. We will also analyze GPR65 expression and the cytokine secretion capacity of macrophages from healthy blood donors and TAMs in CRC samples from non-obese and obese patients; 2) Identify the mechanism by which HFD promotes GPR65 signaling in CRC TAMs by testing the ability of HFD and oleic acid, a dietary triglyceride that is highly enriched in HFD tumors, to alter the oxidative potential, fatty acid oxidation capacity and acid production of human tumor cells via flow cytometry, CyTOF and Seahorse assays. We will also determine if a high-oleic-acid diet is sufficient to modify GPR65 expression and cytokine production by TAMs, and examine if tumor acidity is required for the blunted inflammatory response of TAMs; and verify the role of GPR65 in human macrophages and 3) Assess the effects of targeting GPR65 for tumor immunotherapy in obese and nonobese mice with CRC and other tumor types, namely hepatocellular carcinoma and melanoma, and assess the effects of checkpoint blocking antibodies on tumor growth and anti- tumor immunity in GPR65+ and GPR-/- mice bearing these tumors. The results of these studies are expected to not only reveal a critical mechanism responsible for accelerated tumor growth in the setting of obesity, but also identify a novel target for the treatment of these cancers.

项目摘要/摘要 结直肠癌（CRC）是美国癌症死亡率的第二大主要原因，肥胖症是肥胖症 影响40％的人口，不仅增加了发展CRC的风险，而且增加了CRC死亡率 通过未知的机制。我们的初步研究表明，CRC在呈现的小鼠中生长更快 通过高脂肪饮食（HFD）肥胖，这些小鼠中肿瘤相关的巨噬细胞（TAM）表现出 酸感应受体GPR65的较​​高表达，已知会抑制免疫反应。 此外，在缺乏GRP65的HFD诱导的肥胖小鼠中，TAMS分泌更多的TNF-α和肿瘤生长。 鉴于肥胖小鼠的TAM但不是正常的组织巨噬细胞暴露了GPR65，我们检查了 这些小鼠的肿瘤的pH值，发现它们更酸性。根据这些发现，我们假设 超过HFD中的脂质改变了肿瘤细胞代谢，导致酸产生增加，这增强了 TAM中的GPR65表达和信号传导，导致它们成为免疫抑制并促进肿瘤 生长。为了检验这一假设，我们将追求以下特定目的：1）确定 GPR65在肥胖条件下向TAM功能和CRC生长发出信号，通过确定cAMP是否存在 PKA信号轴在GPR65下游起作用，在肥胖小鼠的TAM和对照中激活 TNF-α产生。我们还将分析巨噬细胞的GPR65表达和细胞因子分泌能力 来自非肥胖和肥胖患者的CRC样品中的健康献血者和TAM； 2）确定 HFD通过测试HFD和油酸的能力来促进CRC TAM中GPR65信号传导的机制 酸是一种高度富集HFD肿瘤的饮食甘油三酸酯，以改变氧化潜力，脂肪酸 通过流式细胞仪，细胞和海马测定法，人类肿瘤细胞的氧化能力和酸产生。 我们还将确定高油酸饮食是否足以改变GPR65表达和细胞因子的产生 通过TAM，检查TAM的炎症反应是否需要肿瘤酸度；并验证 GPR65在人类巨噬细胞中的作用和3）评估靶向GPR65肿瘤的影响 具有CRC和其他肿瘤类型的肥胖和非肥胖小鼠的免疫疗法，即肝细胞 癌和黑色素瘤，并评估检查点阻断抗体对肿瘤生长和抗 - 的影响 具有这些肿瘤的GPR65+和GPR - / - 小鼠中的肿瘤免疫。这些研究的结果有望 不仅揭示了肥胖环境中造成肿瘤生长加速的关键机制，而且还 确定治疗这些癌症的新目标。