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

胰腺导管腺癌(PDAC)是导致癌症的主要原因之一。 相关死亡。这是由于疾病的早期阶段没有症状， 肿瘤的纤维化性质，以及对手术、化疗和 免疫疗法。对免疫疗法缺乏反应是尽管事实是 胰腺癌表现出明显的免疫浸润性。相对较少的是 了解PDAC的免疫状况，但很明显，抑制性 巨噬细胞群可能在肿瘤的形成中起关键作用。 微环境和靶向可能影响对治疗的反应。同样， 微生物群活动的改变与胰腺癌的进展有关， 对免疫治疗的抵抗力，以及患者的生存时间。最近我们 描述了芳香烃受体(AhR)作为驱动因素的关键作用 巨噬细胞抑制功能。由于AhR是微生物的重要传感器 代谢产物，我们推测微生物群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；同时阻止AhR 活动会使肿瘤微环境变得“热”增强 对标准护理化疗和免疫治疗的反应。这样做的目的是 建议调查微生物群如何改变肿瘤中的免疫。 微环境。为了实现这一目标，我们开发了一种原位小鼠 PDAC的模型。我们的初步数据表明，AhR对肿瘤至关重要。 乳杆菌菌种驱动生长及其产生的特定代谢物 抑制巨噬细胞功能，抑制T细胞炎症成熟。在……里面 目前的建议，我们将机械地调查如何调制 巨噬细胞通过AhR在肿瘤微环境中发挥作用。到时候我们会的 验证阻断AhR将改善肿瘤对 吉西他滨和检查点抑制剂治疗，最后我们将测试预测 在小鼠模型中产生的人巨噬细胞，并检查 微生物组、AhR活性与PDAC患者生存的相关性。 该提案中概述的实验将确立重要的生物学原理。 并在微生物群之间提供了一种新的机械联系：肿瘤相互作用 促进生长和转移。归根结底，我们的机制和范式 揭示有潜力导致治疗PDAC的新策略，并显著 影响这种可怕疾病的临床结果。

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.