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

胰腺导管腺癌（PDAC）是癌症的主要原因之一- 相关死亡这是由于疾病的早期阶段无症状， 肿瘤的纤维化性质，以及对手术、化疗和化疗缺乏反应， 免疫疗法尽管事实上， 胰腺癌表现出显著的免疫浸润。之甚少 了解PDAC中的免疫景观，但很明显， 巨噬细胞群可能在形成肿瘤中起关键作用 微环境和靶向它们可能会影响对治疗的反应。同样地， 改变的微生物组活性与胰腺癌进展有关， 对免疫治疗的抵抗力和患者的存活时间。最近我们 描述了芳香烃受体（AhR）作为驱动剂的关键作用， 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，我们推测微生物组可能驱动肿瘤巨噬细胞 通过植物群产生的代谢产物发挥作用;同时阻断AhR 活性将导致肿瘤微环境变得“热”增强 对标准化疗和免疫疗法的反应。这个目标 该提案旨在研究微生物组如何改变肿瘤中的免疫力 微环境为了实现这一目标，我们开发了一种原位小鼠 PDAC模型我们的初步数据表明，AhR是关键的肿瘤 生长和特定的代谢产物产生的乳酸杆菌种驱动 巨噬细胞抑制功能和抑制T细胞炎性成熟。在 目前的建议，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。然后我们将 研究阻断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 在人类巨噬细胞的小鼠模型中产生，并检查 PDAC患者的微生物组、AhR活性和生存率之间的相关性。 这项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新的机制联系：肿瘤相互作用， 促进生长和转移。最终，我们所使用的机制和模式 揭示有可能导致新的策略来治疗PDAC， 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.