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.
摘要
最近的临床前研究表明,辅助性CD4+T辅助细胞(Th)和CD8+细胞的不同亚群
T细胞毒性(TC)细胞有望在过继细胞治疗(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久性,并导致肿瘤控制的改善,如
与Th1亚群(分泌干扰素γ、白介素2、肿瘤坏死因子α)比较。然而,与这些观察相反的是,
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,亚群对控制肿瘤的反应是复杂的
很大一部分肿瘤反应性T细胞获得FoxP3+调节表型,变得功能障碍或
经历细胞死亡,导致肿瘤逆转。因此,体外编程条件可以使T细胞成为
稳定的表型,不仅能控制原发肿瘤,还能形成抗肿瘤
记忆对于ACT来说将是极其重要的。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“干细胞性”结合在一起,可以产生更好的
表现出长期肿瘤控制的混合Th1/17细胞。重要的是,这些体外编程条件也
产生高效的Tc1/Tc17杂交细胞并产生人肿瘤浸润性淋巴细胞
细胞因子分泌能力增强。重要的是,杂交T细胞表现出更高水平的烟酰胺
腺二核苷酸(NAD+),一种辅因子,作为sirtuins的底物,调节多种代谢
和表观遗传分子。我们假设用杂交药观察到了强健的长期肿瘤控制
Th1/17细胞是由高NAD+导致的T细胞表型全面恢复所介导的。
包括翻译后修饰和表观遗传稳定性在内的事件组合导致
符合新陈代谢的表型。鉴于NAD+在包括能源在内的各种生物过程中的关键作用
新陈代谢、衰老、钙稳态和表观基因组,我们提出以下目的来检验上述问题
假设:目的1)确定细胞因子亚群的代谢特征和抗肿瘤表型
杂交T1/17细胞可以被转化为编程肿瘤浸润性淋巴细胞;目的2)确定
抗体介导的CD38与PD1抗体的联合抑制在小鼠体内产生强大的抗肿瘤反应
不同的临床前活体和异种移植模型;以及目的3)确定NAD+水平如何对
代谢-表观遗传规划在T1/17杂交瘤和CD38-KO T中保持强大的抗肿瘤反应
细胞。我们认为,这项确定导致卓越抗肿瘤作用的中心机制的提议
杂交T1/17细胞的反应对于适应这些体外编程条件将是重要的
翻译在过继T细胞免疫治疗中的应用。
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:
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:
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:
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: