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: 10611911
• 负责人: Tracy L McGaha
• 金额: $ 36.37万
• 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/10611911
• 关键词: Aryl Hydrocarbon Receptor; Automobile Driving; Biological; CD8-Positive T-Lymphocytes; Cancer Etiology; Cessation of life; Clinical; Data; Disease; Environment; Exhibits; Fostering; Functional disorder; Gene Expression Profile; Germ-Free; Goals; Growth; Human; Immune; Immune System Diseases; Immunity; Immunooncology; Immunosuppression; Immunotherapy; Indoles; Infiltration; Inflammatory; Investigation; KPC model; Lactobacillus; Learning; Link; Lytic; Macrophage; 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; checkpoint therapy; chemotherapy; experimental study; gemcitabine; gut colonization; gut microbiome; gut microbiota; immune cell infiltrate; immunoregulation; improved; inhibitor; inhibitor therapy; insight; microbial; microbial composition; microbiome; microbiome alteration; microbiota; mouse model; new therapeutic target; novel; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; 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 这归因于疾病的无症状早期阶段，即 肿瘤的纤维化性质，以及对手术、化疗和化疗缺乏反应 尽管事实上，免疫疗法缺乏反应。 胰腺癌表现出显着的免疫浸润。 了解 PDAC 中的免疫状况，但很明显，抑制性 巨噬细胞群可能在肿瘤形成过程中发挥关键作用 微环境和针对它们可能会影响对治疗的反应。 微生物组活动与胰腺癌的进展有关， 最近我们对免疫治疗的抵抗力和患者的生存时间进行了研究。 描述了芳烃受体（AhR）作为驱动因素的关键作用 由于AhR是微生物的重要传感器，因此具有巨噬细胞抑制功能。 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发挥作用，同时阻断 AhR； 活性会导致肿瘤微环境变得“热”增强 对标准护理化疗和免疫疗法的反应这是其目标。 提议是研究微生物组如何改变肿瘤的免疫力 为了实现这一目标，我们开发了原位小鼠。 我们的初步数据表明 AhR 对肿瘤至关重要。 由乳酸菌物种驱动的生长和特定代谢物 巨噬细胞抑制功能并抑制 T 细胞炎症成熟。 目前的提案，我们将机械地研究如何调制 AhR 的巨噬细胞功能发生在肿瘤微环境中。 检查阻断 AhR 将改善肿瘤反应的预测 吉西他滨和检查点抑制剂治疗，最后我们将测试预测 在人类巨噬细胞的小鼠模型中生成并检查 微生物组、AhR 活性和 PDAC 患者生存率之间的相关性。 该提案中概述的实验将建立重要的生物学原理 并提供微生物组与肿瘤相互作用之间的新机制联系 最终，我们的机制和范式促进了生长和转移。 揭示有可能导致治疗 PDAC 的新策略，并显着 影响这种可怕疾病的临床结果。