Interleukin-35 and the tumor microenvironment
Interleukin-35 与肿瘤微环境
基本信息
- 批准号:9306799
- 负责人:
- 金额:$ 38.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAntigensAutoantigensAutoimmune ProcessAutoimmunityCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCTLA4 geneCell CountCell ProliferationCell physiologyClinicalDevelopmentDiseaseEmployee StrikesEventFutureGeneticGenetic TranscriptionHomeostasisHumanImmuneImmunityIn VitroInflammatoryInterleukinsKnock-inKnock-outLinkLongevityMaintenanceMalignant NeoplasmsModelingMusMutant Strains MicePeptidesPhenotypePhysiologicalPopulationPositioning AttributeProductionProtein p53Regulatory T-LymphocyteReporterReportingResearchRoleSuppressor-Effector T-LymphocytesSystemT-LymphocyteTP53 geneTestingTherapeuticTransgenic OrganismsTumor Immunitycancer therapycytokineexhaustionexperimental studyimprovedinhibitor/antagonistnovelpreventprophylacticreceptorreceptor expressiontherapeutic targettherapy outcometooltreatment strategytumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
Inhibitory mechanisms within the tumor microenvironment represent major barriers to effective antitumor
immunity. Although striking efficacy in a variety of tumor types has been reported in clinical trails with inhibitory
receptor blockade, it's clear that additional inhibitory mechanisms will need to be targeted to substantially
improve therapeutic outcome in most tumor types. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor
immunity. Although targeted Treg ablation results in rapid tumor shrinkage in multiple models of human cancer,
this is not a viable therapeutic approach due to the subsequent severe autoimmune and inflammatory
consequences. Thus more targeted approaches to limit Treg activity selectively in the tumor microenvironment
are needed, along with in depth understanding of their mechanism of action. Although Tregs use multiple
inhibitory mechanisms to control T cell function, it is unclear which are dominant in the tumor microenvironment
and thus may be viable therapeutic targets in cancer. Interleukin-35 (IL35), an Ebi3/Il12a heterodimer, is an
inhibitory cytokine produced by Tregs that is a potent suppressor of T cell proliferation and function. Treg-derived
IL35 can also promote the development of an induced regulatory T cell population that suppresses via IL35
(iTr35), which in turn can contribute to the suppressive intratumoral milieu. However, the physiological impact
and mechanism of action of IL35 within the tumor microenvironment are largely unknown. In this competitive
renewal application, we will determine how IL35 modulates the tumor microenvironment.
AIM 1: Dissecting the function and fate of IL35+ Tregs in the tumor microenvironment. Using Ebi3 reporter,
conditional and linage tracing mice, we will determine the physiological importance of IL35 production by Tregs
in tumors and the role and fate of Ebi3+ versus Ebi3– Tregs.
AIM 2: Determining the impact of IL35 on CD8+ T cells within the tumor microenvironment. Using Ebi3
conditional mice, we will determine the impact of Treg-derived IL35 on the function and fate of CD8+ T cells in
tumors.
This project will have a significant impact of our understanding of the physiological importance and
mechanism of action of IL35 in the tumor microenvironment. Given that we discovered IL35 and have
many unique tools to probe its function, we are in the best position to conduct this research.
项目概要
肿瘤微环境内的抑制机制是有效抗肿瘤的主要障碍
免疫。尽管在临床试验中已报道了对多种肿瘤类型的显着疗效,但具有抑制作用
受体阻断,很明显,需要有针对性地采取额外的抑制机制
改善大多数肿瘤类型的治疗效果。调节性 T 细胞 (Treg) 是抗肿瘤的有效抑制剂
免疫。尽管靶向 Treg 消融可导致多种人类癌症模型中的肿瘤快速缩小,
由于随后出现严重的自身免疫和炎症,这不是一种可行的治疗方法
结果。因此,更有针对性的方法可以选择性地限制肿瘤微环境中的 Treg 活性
需要深入了解其作用机制。尽管 Tregs 使用多个
控制 T 细胞功能的抑制机制,目前尚不清楚哪些机制在肿瘤微环境中占主导地位
因此可能是癌症的可行治疗靶点。 Interleukin-35 (IL35) 是一种 Ebi3/Il12a 异二聚体,是一种
由 Tregs 产生的抑制性细胞因子,是 T 细胞增殖和功能的有效抑制剂。 Treg衍生的
IL35 还可以促进诱导性调节性 T 细胞群的发育,通过 IL35 抑制
(iTr35),这反过来又有助于抑制瘤内环境。但生理上的影响
IL35 在肿瘤微环境中的作用机制在很大程度上尚不清楚。在这场竞争激烈的
更新申请后,我们将确定IL35如何调节肿瘤微环境。
目标 1:剖析肿瘤微环境中 IL35+ Tregs 的功能和命运。使用Ebi3记者,
条件和谱系追踪小鼠,我们将确定 Tregs 产生 IL35 的生理重要性
在肿瘤中以及 Ebi3+ 与 Ebi3- Tregs 的作用和命运。
目标 2:确定 IL35 对肿瘤微环境中 CD8+ T 细胞的影响。使用Ebi3
条件小鼠,我们将确定 Treg 衍生的 IL35 对 CD8+ T 细胞的功能和命运的影响
肿瘤。
该项目将对我们对生理重要性的理解产生重大影响,
IL35在肿瘤微环境中的作用机制。鉴于我们发现了 IL35 并且已经
许多独特的工具来探索其功能,我们最有能力进行这项研究。
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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Dario AA Vignali其他文献
The extent of metalloproteinase-mediated LAG3 cleavage limits the efficacy of PD1 blockade
- DOI:
10.1186/2051-1426-3-s2-p216 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Lawrence P Andrews;Andrea L Szymczak-Workman;Creg J Workman;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Remodulation of the tumor microenvironment by regulatory T cells
- DOI:
10.1186/2051-1426-3-s2-p409 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Chang Liu;Maria Chikina;Creg J Workman;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Elucidating the role of Neuropilin-1 in intra-tumoral regulatory T cell stability
- DOI:
10.1186/2051-1426-3-s2-p274 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Abigail E Overacre;Maria Chikina;Greg M Delgoffe;Dario AA Vignali - 通讯作者:
Dario AA Vignali
Antigen presentation by tumor infiltrating B cells influences CD4 T cell phenotype and function in primary lung cancer patient tumors
- DOI:
10.1186/2051-1426-3-s2-p397 - 发表时间:
2015-11-04 - 期刊:
- 影响因子:10.600
- 作者:
Tullia Bruno;Peggy Ebner;Brandon Moore;Daniel Munson;John Mitchell;Jeffrey Kern;Dario AA Vignali;Jill Slansky - 通讯作者:
Jill Slansky
Dario AA Vignali的其他文献
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{{ truncateString('Dario AA Vignali', 18)}}的其他基金
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10454307 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目1:评估LAG3和PD-1在黑色素瘤患者中的协同作用
- 批准号:
10683756 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目 1:评估 LAG3 和 PD-1 在黑色素瘤患者中的协同作用
- 批准号:
10469635 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10298246 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Regulatory T cells and the tumor microenvironment
调节性T细胞和肿瘤微环境
- 批准号:
10670939 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients
项目 1:评估 LAG3 和 PD-1 在黑色素瘤患者中的协同作用
- 批准号:
10270231 - 财政年份:2021
- 资助金额:
$ 38.03万 - 项目类别:
Synergies among inhibitory receptors in tolerance, cancer & antiviral immunity
抑制性受体在耐受性、癌症方面的协同作用
- 批准号:
10470821 - 财政年份:2015
- 资助金额:
$ 38.03万 - 项目类别:
Project 2 - Modulation of Anti-Tumor Immunity by Inhibitory Receptors
项目2——抑制性受体调节抗肿瘤免疫
- 批准号:
10670296 - 财政年份:2015
- 资助金额:
$ 38.03万 - 项目类别:
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