Enhancing the Effectiveness of Immunotherapies by T Cell Epigenetic Reprogramming
通过 T 细胞表观遗传重编程增强免疫疗法的有效性
基本信息
- 批准号:10737264
- 负责人:
- 金额:$ 64.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-05 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdoptive TransferAgonistBackBiological ModelsBreast AdenocarcinomaCD8-Positive T-LymphocytesCRISPR/Cas technologyCTLA4 geneCancer PatientCell physiologyCellsChromatinChronicClinicalDNA MethylationDNMT3aDataEffectivenessEndowmentEnzymesEpigenetic ProcessEquilibriumFailureFunctional disorderGenesGenetic TranscriptionGliomaGoalsGrantHumanImmune responseImmunotherapyIn VitroInfectionKnowledgeLinkLymphocytic choriomeningitis virusMalignant NeoplasmsMediatingMemoryMethodsModelingMolecular TargetMorbidity - disease rateMusNaturePathway interactionsPatientsPre-Clinical ModelRefractoryRejuvenationReportingResistanceRoleRouteSignal PathwaySignal TransductionSpecificitySystemT cell differentiationT-LymphocyteTechnologyTestingTherapeuticTransforming Growth Factor betaTransgenic OrganismsTranslatingViralViral CancerVirusVirus Diseasesantagonistchromatin remodelingchronic infectioncytotoxiccytotoxic CD8 T cellsepigenomeexhaustexhaustionexperimental studyfunctional restorationimmune checkpoint blockadein vitro Modelin vivoin vivo Modelinsightmelanomamortalitynovelnovel strategiespreventprogenitorprogrammed cell death protein 1programsreceptorrefractory cancerresponserestraintretroviral transductionstemstemnesssuccesssynergismtooltranscriptometumor
项目摘要
PROJECT SUMMARY
Cancer and chronic virus infections are significant causes of morbidity and mortality. While cytotoxic CD8 T
cells are the main killers of tumors or virus-infected cells, persistent stimulation of CD8 T cells during chronic
infections or cancer results in a gradual loss of their cytotoxic function as T cells progress towards a fully-
exhausted state. While immune checkpoint blockade (ICB) therapy allows partially-exhausted CD8 T cells to
functionally recover by blocking inhibitory signals, terminally-exhausted T cells remain nonresponsive to this
therapy. The inability of terminally-exhausted T cells to recover after ICB may explain why many cancer patients
fail to mount durable responses to ICB. We recently showed that de novo DNA methylation programming is
causally linked to the progression of T cells toward terminal exhaustion and poor response to ICB. Importantly,
we discovered that targeting T cell-intrinsic epigenetic programs synergized the efficacy of ICB during chronic
infection or cancer. Yet, the following questions represent major gaps in our current understanding of T cell
exhaustion: (1) How are these epigenetic changes acquired in exhausted T cells? (2) What are the upstream
signals that regulate the specificity of de novo DNA methylation programs in exhausted versus functional T cells?
(3) Can we reverse the epigenetic programming in exhausted T cells to the functional state while avoiding
transformation? Bridging these gaps will allow us to identify and target factors that apply “epigenetic brakes” to
CD8 T cell function. To address these questions, we have developed a novel in-vitro model of stable human T
cell dysfunction as a tractable tool that can guide our in-vivo experiments by providing first-line mechanistic
studies. First, we will employ cutting-edge approaches, such as CRISPR-Cas9 gene editing and retroviral
transduction, to test the hypothesis that specific tumor microenvironmental signals regulate epigenetic
programming in persistently stimulated CD8 T cells, which promotes their resistance to ICB therapy. We aim to
block and/or revert the progression toward the terminally-exhausted state by targeting components of this
signaling pathway while promoting counteracting pathways. Second, we aim to rebalance specific
microenvironmental signals to restore functionality and response in terminally-exhausted T cells. Using novel in-
vitro model systems of T cell dysfunction and complementary in-vivo models of chronic viral infection and cancer,
as well as cutting-edge technologies to profile DNA methylation, open chromatin landscape, and transcriptome
in CD8 T cells, our proposed studies can determine if targeting specific factors can remodel chromatin back into
an accessible state at effector and/or stemness-associated genes, leading to functionally-rejuvenated T cells.
These proposed studies will provide insights into how epigenetic programming can be reversed during
progression to T cell exhaustion that can be translated to reprogram terminally-exhausted T cells in clinical
settings, ultimately enhancing the efficacy of T cell immunotherapies.
项目摘要
癌症和慢性病毒感染是发病率和死亡率的重要原因。而细胞毒性CD 8 T
细胞是肿瘤或病毒感染细胞的主要杀手,在慢性炎症期间持续刺激CD 8 T细胞,
感染或癌症导致它们的细胞毒性功能逐渐丧失,因为T细胞向完全-
疲惫的状态。虽然免疫检查点阻断(ICB)疗法允许部分耗尽的CD 8 T细胞,
当通过阻断抑制信号功能恢复时,终末耗竭的T细胞对此保持无应答,
疗法ICB后终末耗竭的T细胞无法恢复可能解释了为什么许多癌症患者
未能对ICB作出持久的反应。我们最近表明,从头DNA甲基化编程是
与T细胞向终末耗竭的进展和对ICB的不良反应有因果关系。重要的是,
我们发现,靶向T细胞内在表观遗传程序协同ICB的疗效,
感染或癌症。然而,以下问题代表了我们目前对T细胞的理解中的主要差距。
耗竭:(1)这些表观遗传变化是如何在耗竭的T细胞中获得的?(2)上游有哪些
信号,调节特异性从头DNA甲基化程序在耗尽与功能性T细胞?
(3)我们能不能在避免T细胞过度增殖的同时,
转化?弥合这些差距将使我们能够识别和瞄准那些对人类的健康施加“表观遗传制动器”的因素。
CD 8 T细胞功能。为了解决这些问题,我们开发了一种新的稳定的人T细胞体外模型,
细胞功能障碍作为一种易于处理的工具,可以通过提供一线机制来指导我们的体内实验
问题研究首先,我们将采用尖端的方法,如CRISPR-Cas9基因编辑和逆转录病毒,
转导,以检验特定肿瘤微环境信号调节表观遗传的假设
在持续刺激的CD 8 T细胞中编程,这促进了它们对ICB疗法的抗性。我们的目标是
阻止和/或逆转向最终耗尽状态的进展,
信号通路,同时促进抵消通路。其次,我们的目标是重新平衡具体的
微环境信号来恢复终末耗尽的T细胞的功能和反应。把小说用在-
T细胞功能障碍的体外模型系统和慢性病毒感染和癌症的补充体内模型,
以及分析DNA甲基化、开放染色质景观和转录组的尖端技术
在CD 8 T细胞中,我们提出的研究可以确定靶向特定因子是否可以将染色质重塑回
在效应子和/或干细胞相关基因处的可接近状态,导致功能再生的T细胞。
这些拟议的研究将提供见解如何表观遗传编程可以逆转,
T细胞耗竭的进展,可转化为临床中终末耗竭的T细胞的重编程
最终增强T细胞免疫疗法的功效。
项目成果
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Hazem E. Ghoneim其他文献
T cell exhaustion—a memory locked behind scars
T 细胞衰竭——锁在伤疤背后的记忆
- DOI:
10.1038/s41590-021-00977-3 - 发表时间:
2021 - 期刊:
- 影响因子:30.5
- 作者:
Amira Yousif;Hazem E. Ghoneim - 通讯作者:
Hazem E. Ghoneim
A Novel Mechanism of Enhanced Susceptibility to Bacterial Pneumonia in Influenza-infected Hosts
流感感染宿主对细菌性肺炎易感性增强的新机制
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Hazem E. Ghoneim - 通讯作者:
Hazem E. Ghoneim
T cell exhaustion is Reinforced by Progressive De novo DNA Methylation Programming
渐进式 DNA 从头甲基化编程强化了 T 细胞耗竭
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:4.4
- 作者:
Ben Youngblood;Hazem E. Ghoneim;Hossam A. Abdelsamed;R. Carter;J. Hale;Eunseon Ahn;Sejin Im;Rafi Ahmed - 通讯作者:
Rafi Ahmed
Superinfections Influenza Infection Facilitates Bacterial Depletion of Alveolar Macrophages during McCullers
重复感染 流感感染促进麦卡勒病期间肺泡巨噬细胞的细菌消耗
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Hazem E. Ghoneim;P. Thomas - 通讯作者:
P. Thomas
Hazem E. Ghoneim的其他文献
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