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。
基本信息
- 批准号:10397510
- 负责人:
- 金额:$ 36.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAryl Hydrocarbon ReceptorAutomobile DrivingBiologicalCD8-Positive T-LymphocytesCancer EtiologyCellsCessation of lifeClinicalDataDiseaseEnvironmentExhibitsFosteringFunctional disorderGene Expression ProfileGerm-FreeGoalsGrowthHumanImmuneImmune System DiseasesImmune checkpoint inhibitorImmunityImmunooncologyImmunosuppressionImmunotherapyIndolesInflammatoryInvestigationKPC modelLactobacillusLeadLinkLyticMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMetabolicMusMyelogenousNatureNeoplasm MetastasisNorth AmericaOperative Surgical ProceduresOutcomePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPeripheral Blood Mononuclear CellPhenotypePlayPopulationProductionReceptor ActivationRefractoryResistanceRoleSeverity of illnessShapesSurvival RateT cell responseT-LymphocyteTestingTherapeutic InterventionTimeTryptophanTumor-infiltrating immune cellsbasecheckpoint therapychemotherapyexperimental studygemcitabinegut colonizationgut microbiotaimmunoregulationimprovedinhibitorinsightmacrophagemicrobialmicrobial compositionmicrobiomemicrobiome alterationmicrobiotamouse modelnew therapeutic targetnovelpancreatic ductal adenocarcinoma modelpancreatic neoplasmpolarized cellpredict clinical outcomeprognostic toolresponsesensorstandard of caretherapeutic targettreatment responsetumortumor growthtumor microbiometumor microenvironmenttumor progression
项目摘要
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,
代谢物,我们推测微生物组可能会驱动肿瘤巨噬细胞
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
并在微生物组与肿瘤相互作用之间提供了一种新的机制联系,
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。
项目成果
期刊论文数量(0)
专著数量(0)
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Tracy L McGaha其他文献
Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy
GCN2 通路的体外激活可代谢重编程 T 细胞,从而增强过继细胞疗法
- DOI:
10.1016/j.xcrm.2024.101465 - 发表时间:
2024 - 期刊:
- 影响因子:14.3
- 作者:
M. St Paul;Samuel D. Saibil;Meghan Kates;SeongJun Han;S. Lien;Rob C Laister;K. Hezaveh;Andreas Kloetgen;Susanne Penny;Tingxi Guo;Carlos R Garcia;Logan K Smith;D. Chung;A. Elford;Azin Sayad;Devanand Pinto;Tak W Mak;Naoto Hirano;Tracy L McGaha;P. Ohashi - 通讯作者:
P. Ohashi
Tracy L McGaha的其他文献
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{{ truncateString('Tracy L McGaha', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 36.93万 - 项目类别:
Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells
IDO、GCN2 和 mTOR 信号在凋亡细胞免疫中的机制关系
- 批准号:
8858718 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells
IDO、GCN2 和 mTOR 信号在凋亡细胞免疫中的机制关系
- 批准号:
9031717 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development
边缘区巨噬细胞和免疫代谢在肿瘤驱动的 MDSC 发育中的作用
- 批准号:
9183751 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development
边缘区巨噬细胞和免疫代谢在肿瘤驱动的 MDSC 发育中的作用
- 批准号:
8886037 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells
IDO、GCN2 和 mTOR 信号在凋亡细胞免疫中的机制关系
- 批准号:
9268408 - 财政年份:2015
- 资助金额:
$ 36.93万 - 项目类别:
The role of GCN2-kinase in antigen presenting cell function and tolerance to self
GCN2激酶在抗原呈递细胞功能和自身耐受性中的作用
- 批准号:
8662697 - 财政年份:2013
- 资助金额:
$ 36.93万 - 项目类别:
The role of GCN2-kinase in antigen presenting cell function and tolerance to self
GCN2激酶在抗原呈递细胞功能和自身耐受性中的作用
- 批准号:
8583790 - 财政年份:2013
- 资助金额:
$ 36.93万 - 项目类别:
Mechanisms of marginal zone macrophage mediated tolerance towards apoptotic cell
边缘区巨噬细胞介导的凋亡细胞耐受机制
- 批准号:
8716373 - 财政年份:2013
- 资助金额:
$ 36.93万 - 项目类别:
The role of indoleamine 2-3 dioxygenase in marginal zone-mediated tolerance
吲哚胺2-3双加氧酶在边缘区介导的耐受中的作用
- 批准号:
8301218 - 财政年份:2011
- 资助金额:
$ 36.93万 - 项目类别:
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