Understanding Metabolic and Epigenetic Cross‐ talk in Potent Anti‐ tumor T cells
了解强效抗肿瘤 T 细胞中的代谢和表观遗传交叉对话
基本信息
- 批准号:10163144
- 负责人:
- 金额:$ 46.37万
- 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:2020-05-12 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAdoptive Cell TransfersAdoptive TransferAgingAntibodiesAntigensAntitumor ResponseAutologousBiological ProcessCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCalciumCell DeathCellsChromatinClinicalDataDeacetylationDependenceEnergy MetabolismEpigenetic ProcessEpitopesEquilibriumEventExhibitsFOXP3 geneFailureFunctional disorderGlutamineHelper-Inducer T-LymphocyteHistone DeacetylaseHomeostasisHumanHuman EngineeringHybridsHydrolaseIL2 geneImmune systemImmunotherapyInterferon Type IIInterleukin-17InvestigationLeadMalignant NeoplasmsMediatingMemoryMetabolicMetabolismMethylationModalityModificationMolecularMusNatural Killer CellsNicotinamide adenine dinucleotidePD-1 blockadePPBP genePatientsPhenotypePost-Translational Protein ProcessingPrimary NeoplasmPropertyProteinsProtocols documentationPublishingRegulationRegulatory T-LymphocyteReporterReportingRoleSIRT1 geneSirtuinsSolid NeoplasmT cell responseT cell therapyT memory cellT-LymphocyteT-Lymphocyte SubsetsTC1 CellTNF geneTestingTh1 CellsTransferaseTranslatingTumor-Infiltrating LymphocytesWorkXenograft Modelanti-PD1 antibodiesbasecancer therapyclinical practicecofactorcombinatorialcytokineengineered T cellsepigenomeexhaustiongenetic signatureimprovedimproved outcomein vivoinfectious disease modelmetabolic profilemitochondrial metabolismmouse modelneoplasm immunotherapynovelpre-clinicalpreclinical studypreservationprogrammed cell death protein 1programsreceptorresponsestem cell fatestem-like cellstemnesstranscriptome sequencingtumortumor growthtumor microenvironment
项目摘要
ABSTRACT
Recent preclinical studies have shown that different subsets of both helper CD4+ T helper (Th) cells and CD8+
T cytotoxic (Tc) cells hold promise for clinical use in adoptive cell therapy (ACT) protocols. Importantly, T
helper cell subsets with the ability to secrete IL-17 (Th17) have been shown to possess stem cell like
phenotype that attributes to their long-term persistence and leads to improved tumor control tumors as
compared to the Th1 subsets (that secrete IFNγ, IL2, TNFα). However, contrary to these observations there
are reports that Tc1 cells exhibit improved tumor control as compared to Tc17 cells. These differences in T cell
subsets response to control tumors is compounded by the fact that in the suppressive tumor microenvironment
a large fraction of tumor reactive T cells acquire FoxP3+ regulatory phenotype, become dysfunctional or
undergo cell death leading to tumor reversion. Thus, ex vivo programming conditions that can render T cells a
stable phenotype, which not only controls primary tumors but also results in the formation of anti-tumor
memory will be of immense importance for ACT. We have recently established that programming conditions
that bring together ‘anti-tumor effector function’ of Th1 cells and ‘stemness’ of Th17 cells lead to a superior
hybrid Th1/17 cells exhibiting long-term tumor control. Importantly, these ex vivo programming conditions also
generate highly effective hybrid Tc1/Tc17 cells and render human tumor infiltrating lymphocytes (TILs) with
increased cytokine secreting ability. Importantly, the hybrid T cells exhibited higher levels of nicotinamide
adenine dinucleotide (NAD+), a cofactor that serves as substrate for Sirtuins and regulates multiple metabolic
and epigenetic molecules. We hypothesize that the robust long-term tumor control was observed with hybrid
Th1/17 cells was mediated by an overall rejuvenated T cell phenotype due to high NAD+ that influenced a
combination of events including post-translational modifications, and epigenetic stability that led to
metabolically fit phenotype. Given the crucial role of NAD+ in a variety of biological processes including energy
metabolism, aging, calcium homeostasis, and epigenome, we propose the following aims to test the above
hypothesis: Aim 1) To determine if metabolic signature and anti-tumor phenotype of the cytokine subsets in
hybrid T1/17 cells could be translated to program tumor infiltrating lymphocytes; Aim 2) To determine if
antibody mediated combinatorial inhibition of CD38 with PD1 antibody leads to robust anti-tumor response in
different preclinical in vivo and xenograft models; and Aim 3) To determine how NAD+ level contributes to
metabolo-epigenetic programming that preserves robust anti-tumor response in T1/17 hybrid and CD38-KO T
cells. We believe that this proposal to determine the central mechanism that results in superior anti-tumor
response by hybrid T1/17 cells will be important to adapt these ex vivo programming conditions for immediate
translational use in adoptive T-cell immunotherapy.
抽象的
最近的临床前研究表明,辅助 CD4+ T 辅助 (Th) 细胞和 CD8+ 细胞的不同亚群
T 细胞毒性 (Tc) 细胞有望在过继细胞疗法 (ACT) 方案中得到临床应用。重要的是,T
具有分泌 IL-17 (Th17) 能力的辅助细胞亚群已被证明具有干细胞样
表型归因于它们的长期持续性并导致改善的肿瘤控制
与 Th1 亚群(分泌 IFNγ、IL2、TNFα)相比。然而,与这些观察相反
有报道称,与 Tc17 细胞相比,Tc1 细胞表现出更好的肿瘤控制能力。 T细胞的这些差异
在抑制性肿瘤微环境中,亚群对对照肿瘤的反应更加复杂
大部分肿瘤反应性 T 细胞获得 FoxP3+ 调节表型,变得功能失调或
经历细胞死亡导致肿瘤逆转。因此,离体编程条件可以使 T 细胞成为
稳定的表型,不仅能控制原发肿瘤,还能导致抗肿瘤细胞的形成
记忆对于 ACT 来说非常重要。我们最近确定了编程条件
将 Th1 细胞的“抗肿瘤效应功能”和 Th17 细胞的“干性”结合在一起,产生了优越的效果
混合 Th1/17 细胞表现出长期肿瘤控制作用。重要的是,这些离体编程条件还
产生高效的杂交 Tc1/Tc17 细胞,并用人肿瘤浸润淋巴细胞 (TIL) 进行渲染
细胞因子分泌能力增加。重要的是,杂交 T 细胞表现出更高水平的烟酰胺
腺嘌呤二核苷酸 (NAD+),一种辅助因子,作为 Sirtuins 的底物并调节多种代谢
和表观遗传分子。我们假设通过混合疗法观察到了强有力的长期肿瘤控制
Th1/17 细胞是由整体恢复活力的 T 细胞表型介导的,这是由于高 NAD+ 影响了
包括翻译后修饰和表观遗传稳定性在内的事件组合
代谢适合的表型。鉴于 NAD+ 在包括能量在内的多种生物过程中发挥着至关重要的作用
新陈代谢、衰老、钙稳态和表观基因组,我们提出以下目标来测试上述内容
假设:目标 1) 确定细胞因子亚群的代谢特征和抗肿瘤表型是否
杂交 T1/17 细胞可被转化为程序化肿瘤浸润淋巴细胞;目标 2) 确定是否
抗体介导的 CD38 与 PD1 抗体的组合抑制可在
不同的临床前体内和异种移植模型;目标 3) 确定 NAD+ 水平如何有助于
代谢表观遗传编程可在 T1/17 杂交和 CD38-KO T 中保持强大的抗肿瘤反应
细胞。我们相信这一提议确定了产生优越抗肿瘤作用的中心机制
杂交 T1/17 细胞的反应对于适应这些离体编程条件以立即实现这一目标非常重要。
过继性 T 细胞免疫疗法中的转化应用。
项目成果
期刊论文数量(0)
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Shikhar Mehrotra其他文献
Shikhar Mehrotra的其他文献
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{{ truncateString('Shikhar Mehrotra', 18)}}的其他基金
Increasing Thiols for Improving T cell Immunotherapy
增加硫醇以改善 T 细胞免疫治疗
- 批准号:
10603006 - 财政年份:2022
- 资助金额:
$ 46.37万 - 项目类别:
Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity
RNA结合蛋白和T细胞在口腔上皮可塑性中的交叉点
- 批准号:
10417171 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Understanding Metabolic and Epigenetic Cross‐ talk in Potent Anti‐ tumor T cells
了解强效抗肿瘤 T 细胞中的代谢和表观遗传交叉对话
- 批准号:
10400117 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity
RNA结合蛋白和T细胞在口腔上皮可塑性中的交叉点
- 批准号:
10178000 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Programming Metabolically Fit TILs for Immunotherapy
为免疫疗法编程适合代谢的 TIL
- 批准号:
9906726 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Understanding Metabolic and Epigenetic Cross‐ talk in Potent Anti‐ tumor T cells
了解强效抗肿瘤 T 细胞中的代谢和表观遗传交叉对话
- 批准号:
10599308 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Intersections of RNA-binding proteins and T-cells in oral epithelial plasticity
RNA结合蛋白和T细胞在口腔上皮可塑性中的交叉点
- 批准号:
10632129 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Programming Metabolically Fit TILs for Immunotherapy
为免疫疗法编程适合代谢的 TIL
- 批准号:
10822377 - 财政年份:2020
- 资助金额:
$ 46.37万 - 项目类别:
Anti-oxidant and Metabolic Phenotype in Regulating Tumor Specific T cell Memory Response
抗氧化和代谢表型调节肿瘤特异性 T 细胞记忆反应
- 批准号:
10300448 - 财政年份:2019
- 资助金额:
$ 46.37万 - 项目类别:
Anti-oxidant and Metabolic Phenotype in Regulating Tumor Specific T cell Memory Response
抗氧化和代谢表型调节肿瘤特异性 T 细胞记忆反应
- 批准号:
9917102 - 财政年份:2019
- 资助金额:
$ 46.37万 - 项目类别:














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