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: 10706825
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 23.18万
• 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/10706825
• 关键词: Acceleration; Acids; Address; Adult; Affect; African American; Asian; Body mass index; Breast Carcinoma; Cancer Patient; Cells; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Colorectal Cancer; Consultations; Coupled; Cytometry; Data; Detection; Disease; Ethnic Origin; Fatty Acids; Frequencies; Functional disorder; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Growth; High Fat Diet; High Prevalence; Hispanic; Hispanic Populations; Human; Immune; Incidence; Learning; Lipids; Macrophage; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Maps; Molecular; Mus; Non obese; Not Hispanic or Latino; Obese Mice; Obesity; Obesity associated cancer; Oleic Acids; Pancreatic Adenocarcinoma; Patients; Phenotype; Play; Population; Primary carcinoma of the liver cells; Production; Race; Risk; Risk Factors; Role; Sampling; Signal Transduction; Surface; TNF gene; Testing; Therapeutic Intervention; Time; Tissues; Tumor Immunity; Tumor-associated macrophages; Tumor-infiltrating immune cells; Weight; cancer health disparity; cytokine; diet-induced obesity; experience; experimental study; indexing; innate immune mechanisms; lipid metabolism; malignant breast neoplasm; molecular targeted therapies; mouse model; neoplasm immunotherapy; neoplastic cell; new therapeutic target; novel; obese patients; obesogenic; parent grant; parent project; single-cell RNA sequencing; spatial relationship; tumor; tumor growth; tumor metabolism; tumor microenvironment

Supplement Project Summary Obesity (body mass index ≥30 kg/m2), which affects at least one-third of the U.S. population, is more prevalent among African American and Hispanic populations and increases the risks of both developing and dying from certain cancers. However, the cellular and molecular mechanisms underlying these risks are unknown. Our studies demonstrate that colorectal cancer (CRC) and other tumors grow considerably faster in diet-induced obese mice due to the immunosuppressive actions of the acid-sensing receptor, G-protein coupled 65 (GPR65), on tumor-associated macrophages (TAMs). In the parent project, we are analyzing the intracellular signals from GPR65 that alter TAM function and tumor growth in obese mice, identifying the mechanism by which a high-fat diet (HFD) promotes GPR65 signaling in TAMs, and assessing the effects of targeting GPR65 for tumor immunotherapy in obese and non-obese mice. Data from the parent project indicate that altered lipid metabolism is responsible for upregulating GPR65 expression on TAMs in the tumors of obese mice. Since the lipid profile in tumors of obese humans is nearly identical to that of tumors from obese mice, we believe there is a high likelihood that tumors from obese humans will display a similar immune profile. In the proposed supplement project, we will extend our studies to human cancers including CRC, hepatocellular carcinoma (HCC), pancreatic adenocarcinoma (PDAC) and breast carcinomas in order to test the hypothesis that GPR65 expression on TAMs is associated with obesity, altered TAM function and alterations of other immune cells in the tumor microenvironment. We further hypothesize that these effects of obesity on immune cells in cancer are equivalent in African American, Hispanic, Asian and non-Hispanic White populations and not determined on the basis of race or ethnicity. To analyze the tumors, we will use mass cytometry (CyTOF) to examine the frequencies, surface, and cytokine profiles of immune cells in the tumor, use single cell RNA sequencing (scRNA seq) to analyze the functional profiles of these cells and use CODEX to analyze the spatial relationships between TAMs and other immune cells. We will then compare the results between tumors from patients of different racial and ethnic backgrounds. The results of these experiments are expected to confirm both of our hypotheses and provide a strong rationale for future studies in which these hypotheses are tested in larger populations, and novel therapies targeting GPR65 are developed and evaluated in clinical trials.

补充项目摘要 肥胖（体重指数≥30kg/m2），影响至少三分之一的美国人群，更普遍 在非裔美国人和西班牙裔人群中，增加了发展和死亡的风险 某些癌症。但是，这些风险背后的细胞和分子机制尚不清楚。我们的 研究表明，结直肠癌（CRC）和其他肿瘤在饮食诱导的 肥胖小鼠由于酸性受体的免疫抑制作用，G蛋白耦合65（GPR65）， 在肿瘤相关的巨噬细胞（TAM）上。在父项目中，我们正在分析来自 GPR65改变了肥胖小鼠的TAM功能和肿瘤生长，确定了高脂的机制 饮食（HFD）促进TAM中的GPR65信号传导，并评估靶向GPR65的肿瘤的影响 肥胖和非肥胖小鼠的免疫疗法。来自父项目的数据表明脂质代谢改变了 负责肥胖小鼠肿瘤中TAM上的GPR65表达。由于脂质剖面 在肥胖人类的肿瘤中，人类几乎与肥胖小鼠的肿瘤相同，我们认为有一个很高的 来自肥胖人类的肿瘤的可能性可能会显示出类似的免疫特征。在拟议的补充剂中 项目，我们将把研究扩展到包括CRC，肝细胞癌（HCC），胰腺的人类癌症 腺癌（PDAC）和乳腺癌，以检验taM上GPR65表达的假设 与肥胖，TAM功能改变以及肿瘤中其他免疫细胞的改变有关 微环境。我们进一步假设肥胖对癌症免疫细胞的影响是等效的 在非裔美国人，西班牙裔，亚洲和非西班牙裔白人种群中，并未根据 种族或种族。为了分析肿瘤，我们将使用质量细胞仪（CYTOF）检查频率， 肿瘤中免疫细胞的表面和细胞因子谱，使用单细胞RNA测序（SCRNA SEQ） 分析这些单元的功能曲线，并使用Codex分析TAM之间的空间关系 和其他免疫细胞。然后，我们将比较来自不同种族患者和 种族背景。这些实验的结果有望确认我们的假设和 为未来的研究提供了一个有力的理由，其中这些假设在较大的人群中进行了测试，并且新颖 靶向GPR65的疗法在临床试验中开发和评估。