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)是一种对治疗反应较差的侵袭性恶性肿瘤,
其特征在于免疫细胞的显著浸润。特别是,巨噬细胞丰富的内
PDAC中的肿瘤微环境(TME),并有助于疾病进展和治疗抗性。
然而,影响免疫细胞(包括巨噬细胞)募集和分布的因素,
PDAC在很大程度上仍然未知。最近,我们在项目1中的合作者发现,
Trp 53状态表现出不同的免疫特征。我们的合作者进一步观察到,
(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
由肿瘤的免疫成分形成。我们假设癌细胞的体细胞改变,
起源类型和肿瘤分子亚型影响TME内和整个TME的免疫景观。
在PDAC进展期间的宿主。为了验证这一假设,我们将确定免疫细胞的频率,
分布,并在TME和整个主机中使用高维分析工具(CODEX
和CyTOF)在PDAC的基因工程小鼠模型(GEMM)上的应用,
和细胞来源类型(由项目1开发)。此外,我们将使用分子方法来识别
在不同基因突变的背景下调节免疫细胞募集的免疫调节因子,
细胞类型的起源,我们将使用遗传,药理学和中和抗体为基础的方法,
证实这些因素在推动PDAC进展中的功能作用。重要的是,我们将验证
在人PDAC标本和人胰腺导管细胞系中进行的这些研究的结果
细胞最后,我们最近发现模式识别受体Dectin-2在肿瘤细胞上表达,
相关的巨噬细胞(TAM)在侵袭性的,可移植的PDAC模型。值得注意的是,
天然Dectin-2配体通过重编程以T细胞依赖性方式诱导持续的PDAC消退
将免疫抑制性TAM转化为免疫刺激性抗原呈递细胞(APC)。我们假设
PDAC可以通过将Dectin-2+ TAM重编程为免疫刺激性APC来有效治疗。我们将
用Dectin-2配体治疗由项目1开发的GEMM中产生的自体肿瘤,以测试这一点
假说.此外,为了鉴定Dectin-2刺激在治疗上有效的机制,
我们将使用CODEX和CyTOF观察TME内发生的免疫景观变化,
在治疗过程中,分子方法将被用于识别免疫调节因子
负责调节治疗效果。总之,这些研究将提高我们对
免疫系统在PDAC发育过程中在基因突变、细胞凋亡和细胞凋亡的变化的背景下发生改变。
起源类型和分子亚型,以及对TAM重编程的应答。
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:
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:
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:
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
-
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
-
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
-
批准号:32000851
-
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: