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 在美国，结直肠癌(CRC)是癌症死亡的第二大原因，肥胖症是 影响40%的人口，不仅增加了患结直肠癌的风险，还增加了结直肠癌的死亡率 通过未知的机制。我们的初步研究表明，在渲染的小鼠中，CRC生长得更快 这些小鼠的肿瘤相关巨噬细胞(TAM)表现出 高表达的酸感受器，GPR65，这是已知的抑制免疫反应。 此外，在缺乏GRP65的高脂饮食诱导的肥胖小鼠中，TAMs分泌更多的肿瘤坏死因子-α，肿瘤生长被抑制。 考虑到肥胖小鼠的TAMs而不是正常组织的巨噬细胞表现出GPR65的增加，我们研究了 对这些小鼠体内的肿瘤进行PH值检测，发现它们的酸性更强。根据这些发现，我们假设 HFD中过多的脂质会改变肿瘤细胞的新陈代谢，导致产酸增加，从而增强 GPR65在TAMs中的表达和信号转导，导致其免疫抑制并促进肿瘤 成长。为了检验这一假设，我们将追求以下具体目标：1)确定 GPR65信号转导功能及肥胖条件下结直肠癌生长的研究 在肥胖小鼠和对照组的TAM中，作用于GPR65下游的PKA信号轴被激活 产生肿瘤坏死因子-α。我们还将分析GPR65的表达和巨噬细胞分泌细胞因子的能力 来自健康献血者和非肥胖和肥胖患者结直肠癌样本中的TAM；2)识别 HFD和油酸促进结直肠癌TAM GPR65信号转导的机制 酸，一种在HFD肿瘤中高度富含的饮食甘油三酯，可以改变氧化潜能，脂肪酸 用流式细胞术、细胞周期和海马法测定人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的表达和细胞因子的产生 TAMS，并检查TAMS钝化的炎症反应是否需要肿瘤酸性；以及验证 GPR65在人巨噬细胞中的作用和3)靶向GPR65对肿瘤的影响 肥胖和非肥胖小鼠结直肠癌和其他肿瘤类型即肝细胞癌的免疫治疗 肿瘤和黑色素瘤，并评估检查点阻断抗体对肿瘤生长和抗 GPR65+和GPR-/-荷瘤小鼠的肿瘤免疫功能。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。