Mechanistic investigations of microbiome-driven aryl hydrocarbon receptor activity and macrophage function in pancreatic cancer.

胰腺癌中微生物驱动的芳烃受体活性和巨噬细胞功能的机制研究。

• 批准号: 10397510
• 负责人: Tracy L McGaha
• 金额: $ 36.93万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397510
• 关键词: Address; Aryl Hydrocarbon Receptor; Automobile Driving; Biological; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Clinical; Data; Disease; Environment; Exhibits; Fostering; Functional disorder; Gene Expression Profile; Germ-Free; Goals; Growth; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immunity; Immunooncology; Immunosuppression; Immunotherapy; Indoles; Inflammatory; Investigation; KPC model; Lactobacillus; Lead; Link; Lytic; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Mus; Myelogenous; Nature; Neoplasm Metastasis; North America; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Production; Receptor Activation; Refractory; Resistance; Role; Severity of illness; Shapes; Survival Rate; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tryptophan; Tumor-infiltrating immune cells; base; checkpoint therapy; chemotherapy; experimental study; gemcitabine; gut colonization; gut microbiota; immunoregulation; improved; inhibitor; insight; macrophage; microbial; microbial composition; microbiome; microbiome alteration; microbiota; mouse model; new therapeutic target; novel; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; polarized cell; predict clinical outcome; prognostic tool; response; sensor; standard of care; therapeutic target; treatment response; tumor; tumor growth; tumor microbiome; tumor microenvironment; tumor progression

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer- related death. This is attributable to the asymptomatic early stages of disease, the fibrotic nature of the tumor, and the lack of response to surgery, chemo- and immunotherapies. The lack of response to immunotherapy is despite the fact that pancreatic cancer exhibits a significant immune infiltrate. Relatively little is understood about the immune landscape in PDAC, but it is clear that suppressive populations of macrophages likely play a key role in shaping the tumor microenvironment and targeting them could impact responses to therapy. Likewise, altered microbiome activity has been linked to pancreatic cancer progression, resistance to immune therapy, and survival times in patients. Recently we described a critical role for the aryl hydrocarbon receptor (AhR) as a driver of macrophage suppressive function. Since AhR is an important sensor of microbial metabolites, we surmised that the microbiome may drive tumor macrophage function via the metabolic products produced by the flora; while blocking AhR activity would cause the tumor microenvironment to become “hot” enhancing responses to standard-of-care chemotherapy and immunotherapy. The goal of this proposal is to investigate how the microbiome alters immunity in the tumor microenvironment. To achieve this goal, we have developed an orthotopic mouse model of PDAC. Our preliminary data demonstrate that AhR is critical for tumor growth and specific metabolites produced by Lactobacillus species drive macrophage suppressive function and suppress T cell inflammatory maturation. In the current proposal, we will mechanistically investigate how the modulation of macrophage function by AhR occurs in the tumor microenvironment. We will then examine the prediction that blocking AhR will improve tumor responses to gemcitabine and checkpoint inhibitor therapy, and finally we will test predictions generated in the mouse models in human macrophages and examine the correlation between the microbiome, AhR activity, and survival in PDAC patients. The experiments outlined in this proposal will establish important biologic principles and provide a new mechanistic link between microbiome:tumor interactions that fosters growth and metastasis. Ultimately, the mechanisms and paradigms we reveal have the potential to lead to new strategies to treat PDAC and significantly impact clinical outcomes for this terrible disease.

胰腺导管腺癌（PDAC）是癌症的主要原因之一 相关死亡。这归因于无症状的疾病早期阶段， 肿瘤的纤维化性质以及对手术，化学和化学的反应不足 免疫疗法。缺乏对免疫疗法的反应是一个事实，即 胰腺癌表现出明显的免疫浸润。相对较少 了解PDAC的免疫景观，但很明显 巨噬细胞种群可能在塑造肿瘤中起关键作用 微环境和针对它们可能会影响对治疗的反应。同样地， 微生物组活性改变与胰腺癌进展有关， 对免疫疗法的抗性和患者的生存时间。最近我们 描述了芳基烃受体（AHR）的关键作用 巨噬细胞抑制功能。由于AHR是微生物的重要传感器 代谢物，我们推测微生物组可能驱动肿瘤巨噬细胞 通过菌群产生的代谢产物的功能；在阻止AHR的同时 活动会导致肿瘤微环境变得“热”增强 对护理标准化疗和免疫疗法的反应。目标的目标 建议是研究微生物组如何改变肿瘤中的免疫学 微环境。为了实现这一目标，我们开发了一种原位鼠标 PDAC的模型。我们的初步数据表明，AHR对于肿瘤至关重要 生长和特定的代谢产物由乳杆菌驱动 巨噬细胞抑制功能并抑制T细胞炎症成熟。在 当前的提案，我们将机械地调查如何调制 AHR的巨噬细胞功能发生在肿瘤微环境中。然后我们会 检查阻止AHR会改善肿瘤反应的预测 吉西他滨和检查点抑制剂疗法，最后我们将测试预测 在人类巨噬细胞中的小鼠模型中产生并检查 PDAC患者的微生物组，AHR活性和存活之间的相关性。 该提案中概述的实验将建立重要的生物学原理 并提供微生物组之间的新机械联系：肿瘤相互作用 促进生长和转移。最终，我们的机制和范例 揭示有可能导致新的策略来治疗PDAC，并显着地 影响这种可怕疾病的临床结果。