Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy
Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy
批准号:
10456771
负责人:
EDGAR G. ENGLEMAN
金额:
$42.16万
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
项目状态:
未结题
起止时间:
2021-08-01 至 2026-07-31
关键词:
AffectAgonistAntibodiesAntigen-Presenting CellsAutomobile DrivingBase CompositionBiological AssayCDKN2A geneCell LineCellsComplementDNA Sequence AlterationDNA Sequencing FacilityDataDevelopmentDisease ProgressionDuct (organ) structureDuctal Epithelial CellEnvironmentEnzyme-Linked Immunosorbent AssayExhibitsFrequenciesGeneticGenetically Engineered MouseGenomicsGenotypeGoalsGranulocyte-Macrophage Colony-Stimulating FactorGrowthHumanImmuneImmune responseImmune systemImmunobiologyImmunologicsImmunotherapyKRAS2 geneLesionLigandsMADH4 geneMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMethodsModelingMolecularMusMutationOrganismPancreatic Ductal AdenocarcinomaPancreatic ductPattern recognition receptorPharmacologyPropertyQuantitative Reverse Transcriptase PCRResistanceRoleSignal PathwaySpecimenSystemT-Cell ActivationT-LymphocyteTP53 geneTestingTherapeuticTransplantationTreatment EfficacyTumor-DerivedTumor-associated macrophagesTumor-infiltrating immune cellsVariantWorkanalytical toolantitumor effectbasecancer cellcell typecytokinedriver mutationeffective therapyexome sequencinghigh dimensionalityimmune checkpoint blockadeimmune functionimmunoregulationimprovedmacrophagemolecular subtypesmouse dectin-2mouse modelmutational statusneoplastic cellneutralizing antibodypancreatic ductal adenocarcinoma modelpatient populationprogramsreceptorrecruitresponsesingle-cell RNA sequencingtargeted treatmenttherapy resistanttransplant modeltreatment responsetumortumor growthtumor microenvironment
中文摘要
摘要(项目3)
胰腺导管腺癌(PDAC)是一种对治疗反应不佳的侵袭性恶性肿瘤,
以免疫细胞的显著渗透为特征。特别是,巨噬细胞在脑内大量存在。
肿瘤微环境(TME)在PDAC,并有助于疾病的进展和治疗耐药。
然而,影响包括巨噬细胞在内的免疫细胞在体内招募和分布的因素
PDAC在很大程度上仍不为人所知。最近,我们在项目1中的合作者发现,肿瘤在他们的
TrP53状态表现出不同的免疫特征。我们的合作者进一步观察到起源的细胞类型
(腺泡或导管)影响肿瘤分子亚型(经典或基底样),这也是已知的
由肿瘤的免疫成分决定。我们假设癌细胞的体细胞变化,即细胞
起源类型和肿瘤分子亚型影响TME内和整个TME的免疫格局
在PDAC进展过程中的宿主。为了验证这一假设,我们将确定免疫细胞频率,
使用高维分析工具(CODEX)在TME和整个宿主中的分布和功能
和CyTOF)在驱动突变不同的PDAC基因工程小鼠模型(GEMM)上
和来源的细胞类型(由项目1开发)。此外,我们将使用分子方法来鉴定
免疫调节因子在不同基因突变和不同背景下调节免疫细胞募集
细胞类型的起源,我们将使用基于遗传、药物和中和抗体的方法来
确认这些因素在推动PDAC进展中的功能作用。重要的是,我们将验证
这些研究在人PDAC标本和人胰腺导管来源的细胞系中的发现
细胞。最后,我们最近发现,模式识别受体Dectin-2在肿瘤上表达。
相关巨噬细胞(TAM)在侵袭性的,可移植的PDAC模型中。值得注意的是,管理
天然Dectin-2配体通过重编程诱导T细胞依赖的持续性PDAC回归
免疫抑制TAMs转化为免疫刺激性抗原提呈细胞(APC)。我们假设
通过将Dectin-2 TAMs重新编程为免疫刺激APC,可以有效地治疗PDAC。我们会
用Dectin-2配体治疗由项目1开发的GEMM中出现的本土肿瘤以测试这一点
假设。此外,为了确定Dectin-2刺激具有治疗效果的机制,
我们将使用CODEX和CyTOF来观察TME内发生的免疫格局的变化
经治疗后遍及宿主。将使用分子方法来识别免疫调节因子
负责调停治疗效果。总而言之,这些研究将提高我们对
在PDAC发育过程中,免疫系统在遗传突变、细胞变异的背景下发生变化
起源类型,以及分子亚型,并响应的重新编程。
英文摘要
ABSTRACT (Project 3)
Pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy that is poorly responsive to treatment,
is characterized by a prominent infiltration of immune cells. In particular, macrophages are abundant within the
tumor microenvironment (TME) in PDAC and contribute to disease progression and treatment resistance.
However, the factors affecting the recruitment and distribution of immune cells, including macrophages, in
PDAC remain largely unknown. Recently, our collaborators in Project 1 found that tumors differing in their
Trp53 status exhibited different immune profiles. Our collaborators further observed that the cell type of origin
(acinar or ductal) influenced the tumor molecular subtype (classical or basal-like), which is also known to be
shaped by the immune composition of the tumor. We postulate that somatic alterations in cancer cells, the cell
type of origin, and tumor molecular subtype influence the immune landscape within the TME and throughout
the host during PDAC progression. To test this hypothesis, we will determine immune cell frequency,
distribution, and function in the TME and throughout the host using high-dimensional analytical tools (CODEX
and CyTOF) on genetically engineered mouse models (GEMMs) of PDAC that vary in their driver mutations
and cell type of origin (developed by Project 1). Additionally, we will use molecular methods to identify
immunomodulatory factors regulating immune cell recruitment in the context of different genetic mutations and
cell type of origin, and we will use genetic, pharmacological, and neutralizing antibody-based approaches to
confirm the functional effects of these factors in driving PDAC progression. Importantly, we will validate
findings from these studies in human PDAC specimens and in cell lines derived from human pancreatic ductal
cells. Finally, we recently found that the pattern recognition receptor, Dectin-2, is expressed on tumor-
associated macrophages (TAMs) in an aggressive, transplantable model of PDAC. Notably, administration of
natural Dectin-2 ligands induces sustained PDAC regression in a T-cell dependent manner by reprogramming
immunosuppressive TAMs into immunostimulatory antigen-presenting cells (APCs). We hypothesize that
PDAC can be effectively treated by reprogramming Dectin-2+ TAMs into immunostimulatory APCs. We will
treat autochthonous tumors arising in the GEMMs developed by Project 1 with Dectin-2 ligands to test this
hypothesis. Furthermore, to identify mechanisms by which Dectin-2 stimulation is therapeutically efficacious,
we will use CODEX and CyTOF to observe changes to the immune landscape occurring within the TME and
throughout the host upon treatment. Molecular approaches will be used to identify immunomodulatory factors
responsible for mediating therapeutic efficacy. Together, these studies will improve our understanding of how
the immune system is altered during PDAC development in the context of variation in genetic mutations, cell
type of origin, and molecular subtype, and in response to TAM reprogramming.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Project 1 Mouse Models Analysis
-
批准号:10729466
-
项目类别:
-
资助金额:$56.36万
-
财政年份:2023
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Systems Biology of Tumor-Immune-Stromal Interactions in Metastatic Progression
-
批准号:10729464
-
项目类别:
-
资助金额:$191.91万
-
财政年份:2023
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy
-
批准号:10704089
-
项目类别:
-
资助金额:$42.16万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Targeting Lymph Node Dependent Immune Tolerance in Cancer
-
批准号:10210557
-
项目类别:
-
资助金额:$53.17万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Innate Immune Mechanisms Contributing to Cancer Growth in Obesity
-
批准号:10654802
-
项目类别:
-
资助金额:$48.55万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Innate Immune Mechanisms Contributing to Cancer Growth in Obesity
-
批准号:10430268
-
项目类别:
-
资助金额:$48.55万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Innate Immune Mechanisms Contributing to Cancer Growth in Obesity
-
批准号:10278250
-
项目类别:
-
资助金额:$52.61万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Innate Immune Mechanisms Contributing to Cancer Growth in Obesity
-
批准号:10706825
-
项目类别:
-
资助金额:$23.18万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy
-
批准号:10187127
-
项目类别:
-
资助金额:$44.33万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Targeting Lymph Node Dependent Immune Tolerance in Cancer
-
批准号:10366092
-
项目类别:
-
资助金额:$52.36万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Targeting Lymph Node Dependent Immune Tolerance in Cancer
-
批准号:10599941
-
项目类别:
-
资助金额:$52.74万
-
财政年份:2021
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Effects of Maternal Obesity on Offspring Immune System
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批准号:9913383
-
项目类别:
-
资助金额:$19.9万
-
财政年份:2019
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Effects of FLASH Radiation on Cancer and the Immune Response
-
批准号:10599538
-
项目类别:
-
资助金额:$10.51万
-
财政年份:2019
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Effects of FLASH Radiation on Cancer and the Immune Response
-
批准号:10429937
-
项目类别:
-
资助金额:$48.32万
-
财政年份:2019
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Effects of FLASH Radiation on Cancer and the Immune Response
-
批准号:10188463
-
项目类别:
-
资助金额:$49.3万
-
财政年份:2019
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Effects of FLASH Radiation on Cancer and the Immune Response
-
批准号:10665654
-
项目类别:
-
资助金额:$48.32万
-
财政年份:2019
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer
-
批准号:10401797
-
项目类别:
-
资助金额:$41.97万
-
财政年份:2018
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer
-
批准号:9918925
-
项目类别:
-
资助金额:$43.48万
-
财政年份:2018
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Role of Dendritic Cells in Mixed Chimerism and Tolerance
-
批准号:9223664
-
项目类别:
-
资助金额:$39.91万
-
财政年份:2015
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
Applicability of Mouse Breast Cancer Models to Tumor-Immune Network Investigation
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批准号:9121492
-
项目类别:
-
资助金额:$57.05万
-
财政年份:2015
-
负责人:EDGAR G. ENGLEMAN
-
依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
-
批准年份:2020
-
负责人:乔安娜
-
依托单位: