3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation
3-D 空间方法发现恶性转化过程中免疫抑制的基因组效应子
基本信息
- 批准号:10066668
- 负责人:
- 金额:$ 46.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAdrenal Cortex HormonesAffectAllelesAmino Acid SequenceAnatomyBiological AssayBrain NeoplasmsCD8-Positive T-LymphocytesCellsCellular immunotherapyCessation of lifeClinicalClonalityClone CellsCollaborationsCytometryCytotoxic T-LymphocytesDNA Sequence AlterationDataElementsEnvironmentEventEvolutionExpression ProfilingFailureGene ExpressionGeneticGenomicsGliomaGoalsImmuneImmune systemImmunogenomicsImmunohistochemistryImmunologic FactorsImmunologicsImmunosuppressionImmunotherapyIndividualInfiltrationKnowledgeLocationLoss of HeterozygosityMalignant - descriptorMapsMediatingMutationNewly DiagnosedNon-MalignantOther GeneticsPatientsProductionPublishingRecurrenceRecurrent tumorRoleRouteSTAT1 geneSamplingSourceSpecificityT cell therapyT-Cell ReceptorT-LymphocyteTestingTherapeuticTimeTumor-infiltrating immune cellsValidationantigen-specific T cellsbasecancer genomecell typechemokineclinically significantcohortdesignexome sequencingexperimental studyfitnessgenetic effectorimmunosuppressedimprovedmutantneoantigensneoplastic cellnovelpersonalized medicinepreventtargeted agenttargeted treatmenttranscriptome sequencingtumortumor heterogeneitytumor-immune system interactions
项目摘要
PROJECT SUMMARY/ABSTRACT
Malignant transformation (MT) of IDH-mutant low grade glioma (LGG) to aggressive high grade tumors is an
event of major clinical significance, eventually leading to death in the majority of LGG patients. We discovered
that mutations in IDH promote an immunosuppressed microenvironment characterized by decreased
production of STAT1-regulated chemokines and low CD8+ T cell infiltration in LGG. In malignantly transformed
tumors, we identified the unexpected deletion of the IDH1 mutant allele that may drive counteracting changes
to the immunosuppressed microenvironment specifically during MT. LGG that undergo treatment-induced
hypermutation (HM), another route to MT, produce more high quality neoantigens. Overall in malignantly
transformed tumors relative to patient-matched LGG, we found increasing numbers of T cell clones and
increasing expression of genes involved in cytotoxic T cell attraction and effector function. Based on these
data, we hypothesize that immunosuppression in IDH mutant LGG is reduced upon MT, driven by genetic
alterations that are acquired primarily during malignant transformation. To address this hypothesis, we will
quantify spatial and temporal changes in mutant IDH1-driven immunosuppression during MT (Aim 1). We have
devised a novel 3-dimensional (3-D), tumor-wide approach in which we will acquire 10 spatially mapped
samples per tumor representing maximal anatomy of the tumor. The full cohort will include 30 malignantly
tranformed and 30 non-malignantly transformed recurrences from patients for which we have banked samples
of the matching initial IDH1-mutant LGG. We will use a high-sensitivity T cell repertoire assay, cytometry by
Time of Flight (CyTOF), RNAseq based deconvolution, and multiplex immunohistochemistry to map the
immunologic landscape in 3-D, and determine the extent to which mutant IDH1-mediated immunosuppression
is reduced during MT. In Aim 2, we will determine how genetic alterations acquired during MT affect mutant
IDH1-mediated immunosuppression. We will perform deep whole exome sequencing on samples collected in
Aim 1 to map the intratumoral genomic landscape in 3-D during MT. We will test for the local influence of MT-
associated genetic alterations, including high quality neoantigens in hypermutated tumors, deletion of the
mutant IDH1 allele, or other genetic events on immunosuppression. Understanding which genetic events
contribute to changes in immunosuppression is critical for selecting targeted therapies that could synergize
with immunotherapies to prevent or delay MT. To begin to develop T cell based therapies, we will capture
neoepitope-specific T cells, prioritizing those that are present tumor-wide, and determine the
neoepitopes/HLAs they target and the amino acid sequences for corresponding T Cell Receptor (TCR) α- and
β-chains. We will then test the cloned TCR for relative target specificity and activity against neoantigen-
positive patient-specific tumor cells. The 3-D immuno-genomic landscapes across wide swaths of the tumor
will be essential to the design of personalized therapies that have activity against the whole tumor.
项目总结/摘要
IDH突变型低级别胶质瘤(LGG)向侵袭性高级别肿瘤的恶性转化(MT)是一种恶性肿瘤。
具有重大临床意义的事件,最终导致大多数LGG患者死亡。我们发现
IDH的突变促进了免疫抑制的微环境,其特征在于减少了
在LGG中STAT 1调节的趋化因子的产生和低CD 8 + T细胞浸润。在恶性转化
在肿瘤中,我们发现了IDH 1突变等位基因的意外缺失,这可能会导致抵消性变化
免疫抑制的微环境,特别是在MT。经历治疗诱导的LGG
超突变(HM),另一种MT途径,产生更高质量的新抗原。总体而言,
相对于患者匹配的LGG,我们发现T细胞克隆的数量增加,
增加参与细胞毒性T细胞吸引和效应子功能的基因的表达。基于这些
数据,我们假设IDH突变型LGG的免疫抑制在MT后减少,由遗传驱动,
主要在恶性转化期间获得的改变。为了解决这个问题,我们将
量化MT期间突变IDH 1驱动的免疫抑制的空间和时间变化(Aim 1)。我们有
设计了一种新的三维(3-D),肿瘤范围的方法,我们将获得10个空间映射
每个肿瘤的样本代表肿瘤的最大解剖结构。整个队列将包括30个恶性
转化和30例非恶性转化的复发性肿瘤,我们已经储存了这些患者的样本。
与之匹配的IDH 1突变型LGG基因我们将使用高灵敏度的T细胞库测定,通过流式细胞术,
飞行时间(CyTOF)、基于RNAseq的去卷积和多重免疫组织化学来绘制
免疫景观的三维,并确定在何种程度上突变IDH 1介导的免疫抑制
在MT期间减少。在目标2中,我们将确定MT过程中获得的遗传改变如何影响突变体,
IDH 1介导的免疫抑制。我们将对收集的样本进行深度全外显子组测序,
目的1建立MT过程中肿瘤内基因组三维图谱。我们将测试MT的本地影响-
相关的遗传改变,包括高突变肿瘤中的高质量新抗原,
突变IDH 1等位基因或其他遗传事件对免疫抑制的影响。了解哪些遗传事件
有助于免疫抑制的变化对于选择可以协同的靶向治疗至关重要
用免疫疗法来预防或延缓MT为了开始开发基于T细胞的疗法,我们将捕获
新表位特异性T细胞,优先考虑那些存在于肿瘤范围内的T细胞,并确定新表位特异性T细胞的表达。
它们靶向的新表位/HLA和相应的T细胞受体(TCR)α-和β-的氨基酸序列。
β-链。然后,我们将测试克隆的TCR的相对靶特异性和针对新抗原的活性。
阳性患者特异性肿瘤细胞。肿瘤大范围内的三维免疫基因组景观
对于设计针对整个肿瘤的个性化治疗至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph F Costello其他文献
A first look at entire human methylomes
对整个人类甲基化组的初步观察
- DOI:
10.1038/nbt1209-1130 - 发表时间:
2009-12-01 - 期刊:
- 影响因子:41.700
- 作者:
Joseph F Costello;Martin Krzywinski;Marco A Marra - 通讯作者:
Marco A Marra
Comparative epigenomics of leukemia
白血病的比较表观基因组学
- DOI:
10.1038/ng0305-211 - 发表时间:
2005-03-01 - 期刊:
- 影响因子:29.000
- 作者:
Joseph F Costello - 通讯作者:
Joseph F Costello
Joseph F Costello的其他文献
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{{ truncateString('Joseph F Costello', 18)}}的其他基金
3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation
3-D 空间方法发现恶性转化过程中免疫抑制的基因组效应子
- 批准号:
10434045 - 财政年份:2020
- 资助金额:
$ 46.64万 - 项目类别:
3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation
3-D 空间方法发现恶性转化过程中免疫抑制的基因组效应器
- 批准号:
10651651 - 财政年份:2020
- 资助金额:
$ 46.64万 - 项目类别:
3-D spatial approach to discover genomic effectors of immunosuppression during malignant transformation
3-D 空间方法发现恶性转化过程中免疫抑制的基因组效应器
- 批准号:
10183206 - 财政年份:2020
- 资助金额:
$ 46.64万 - 项目类别:
Global Analyses of the Placental Epigenome in Preeclampsia
先兆子痫胎盘表观基因组的整体分析
- 批准号:
9369783 - 财政年份:2017
- 资助金额:
$ 46.64万 - 项目类别:
Global Analyses of the Placental Epigenome in Preeclampsia
先兆子痫胎盘表观基因组的整体分析
- 批准号:
9920738 - 财政年份:2017
- 资助金额:
$ 46.64万 - 项目类别:
Antigens for Molecularly Targeted Vaccines for Progressive Glioma
进行性神经胶质瘤分子靶向疫苗的抗原
- 批准号:
9087366 - 财政年份:2015
- 资助金额:
$ 46.64万 - 项目类别:
Antigens for Molecularly Targeted Vaccines for Progressive Glioma
进行性神经胶质瘤分子靶向疫苗的抗原
- 批准号:
8968177 - 财政年份:2015
- 资助金额:
$ 46.64万 - 项目类别:
Imaging Guided Genomics of Malignant Transformation
恶性转化的影像引导基因组学
- 批准号:
8830326 - 财政年份:2013
- 资助金额:
$ 46.64万 - 项目类别:
Imaging Guided Genomics of Malignant Transformation
恶性转化的影像引导基因组学
- 批准号:
8649030 - 财政年份:2013
- 资助金额:
$ 46.64万 - 项目类别:
Imaging Guided Genomics of Malignant Transformation
恶性转化的影像引导基因组学
- 批准号:
8504835 - 财政年份:2013
- 资助金额:
$ 46.64万 - 项目类别:
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