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: 10654802
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 48.55万
• 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/10654802
• 关键词: Acceleration; 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; Macrophage; Malignant Neoplasms; Mediator; 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 Promotion; Tumor-associated macrophages; United States; anti-PD-1; 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; melanoma; mortality; mouse model; neoplasm immunotherapy; neoplastic cell; novel; obese patients; obesogenic; overexpression; programmed cell death ligand 1; 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.

项目概要/摘要 结直肠癌 (CRC) 是美国第二大癌症死亡原因，而肥胖则是导致美国癌症死亡的第二大原因。 影响 40% 的人口，不仅增加患 CRC 的风险，还增加 CRC 死亡率 通过未知的机制。我们的初步研究表明，CRC 在小鼠体内生长得更快 通过高脂肪饮食（HFD）导致肥胖，并且这些小鼠中的肿瘤相关巨噬细胞（TAM）表现出 酸敏感受体 GPR65 的表达较高，已知它会抑制免疫反应。 此外，在 HFD 诱导的缺乏 GRP65 的肥胖小鼠中，TAM 会分泌更多的 TNF-α，肿瘤生长会受到抑制。 鉴于肥胖小鼠的 TAM 而不是正常组织巨噬细胞表现出 GPR65 增加，我们检查了 测量这些小鼠肿瘤的 pH 值，发现它们呈酸性。根据这些发现，我们假设 HFD 中过量的脂质会改变肿瘤细胞代谢，导致酸产生增加，从而增强 GPR65 在 TAM 中的表达和信号传导，导致它们变得免疫抑制并促进肿瘤发生 生长。为了检验这一假设，我们将追求以下具体目标：1）确定 通过确定 cAMP- 是否在肥胖条件下 GPR65 向 TAM 功能和 CRC 生长发出信号 PKA 信号轴在 GPR65 下游发挥作用，在肥胖小鼠和对照的 TAM 中被激活 TNF-α 的产生。我们还将分析GPR65的表达和巨噬细胞的细胞因子分泌能力 来自健康献血者和来自非肥胖和肥胖患者的 CRC 样本中的 TAM； 2) 识别 通过测试HFD和油酸的能力，研究HFD促进CRC TAM中GPR65信号传导的机制 酸，一种膳食甘油三酯，在 HFD 肿瘤中高度丰富，可改变氧化电位、脂肪酸 通过流式细胞术、CyTOF 和 Seahorse 测定检测人类肿瘤细胞的氧化能力和产酸能力。 我们还将确定高油酸饮食是否足以改变 GPR65 表达和细胞因子产生 通过TAMs，并检查肿瘤酸度是否是减弱TAMs炎症反应所必需的；并验证 GPR65 在人类巨噬细胞中的作用以及 3) 评估靶向 GPR65 对肿瘤的影响 对患有结直肠癌和其他肿瘤类型（即肝细胞肿瘤）的肥胖和非肥胖小鼠进行免疫治疗 癌症和黑色素瘤，并评估检查点阻断抗体对肿瘤生长和抗肿瘤的影响 携带这些肿瘤的 GPR65+ 和 GPR-/- 小鼠的肿瘤免疫。这些研究的结果预计将 不仅揭示了肥胖背景下肿瘤加速生长的关键机制，而且 确定治疗这些癌症的新靶点。