Role of Tim-3 in determining T cell immunity
Tim-3 在决定 T 细胞免疫中的作用
基本信息
- 批准号:9024492
- 负责人:
- 金额:$ 37.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-01 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgonistAntibodiesAutomobile DrivingBiologyCD8B1 geneCell physiologyCytotoxic T-Lymphocyte-Associated Protein 4DataDevelopmentExhibitsFunctional disorderGenerationsHealthHumanImmune systemImmunityImmunosuppressionImmunotherapeutic agentImmunotherapyKnockout MiceKnowledgeLaboratoriesLifeLymphocyteMalignant NeoplasmsMemoryMorbidity - disease rateMusPathway interactionsPhenotypePopulationPositioning AttributePre-Clinical ModelProcessRegulatory T-LymphocyteRepressionRoleSignal PathwaySignal TransductionT cell responseT cell transcription factor 1T-Cell DevelopmentT-LymphocyteTissuesTumor ImmunityTumor TissueTumor-Infiltrating Lymphocytesadvanced diseasebaseexhaustexhaustionfightingfunctional restorationimprovedmortalitynovelreceptorresponseselective expressiontooltranscription factortumortumor growth
项目摘要
DESCRIPTION (provided by applicant): T cell inhibitory molecules such as CTLA-4, PD-1, and Tim-3 are important regulators of the T cell response that have emerged as valuable immunotherapeutic targets in cancer. Among T cell inhibitory molecules, Tim-3 is now recognized as a critical determinant of the dysfunctional or exhausted CD8+ T cells that arise in cancer. Indeed, we were the first to show that expression of Tim-3 specifically marks the most dysfunctional or exhausted population of CD8+ T cells present in tumor tissue and that immunotherapy that targets Tim-3 markedly improves the efficacy of immunotherapy that targets PD-1 for restoring function to exhausted CD8+ T cells and eliciting potent anti-tumor immunity. We have now discovered that expression of Tim-3 also marks a highly suppressive population of CD4+ FoxP3+ regulatory T cells (Treg) that is uniquely present in tumor tissue. Our preliminary data further indicate that Tim-3 promotes the suppressor function of Treg. Thus, Tim-3 can impact on tumor immunity through its actions in CD8+ T cells and Treg. However, how Tim-3 may function in CD8+ T cells to dampen their responses while in Treg function to promote their suppressive activity is not known. We have now discovered that TCF-1 (T cell factor 1) is specifically down-regulated in Tim-3+ CD8+ tumor- infiltrating lymphocytes (TILs) that exhibit dysfunctional phenotype. Our preliminary data further show that blockade of Tim-3 and PD-1 signaling, which we have shown abrogates T cell exhaustion, restores expression of TCF-1 in Tim-3+ CD8+ TILs. We have further found that TCF-1 is similarly down-regulated in Tim-3+ but not Tim-3- Treg and that Tim-3/PD-1 blockade restores TCF-1 expression in Tim-3+ Treg. TCF-1 is a key transcription factor in the canonical Wnt signaling pathway. TCF-1 is required for normal T cell development and for the generation of long-lived central memory CD8+ T cells but a role for Wnt signaling and TCF-1 in the development of T cell dysfunction/exhaustion has not been addressed. Interestingly, TCF-1 has recently been implicated in antagonizing regulatory T cell function, thus raising the possibility that Tim-3-drivn repression of TCF-1 underlies the potent suppressor function of Tim-3+ Treg. Based on our preliminary data, we hypothesize that Tim-3 suppresses the anti-tumor T cell response via a mechanism that involves repression of Wnt signaling and TCF-1 in intra-tumoral CD8+ T cells and Treg. We are in a unique position to dissect the role of Tim-3 and TCF-1 in determining the anti-tumor T cell response as we have available novel tools, including Tim- 3 and TCF-1 conditional knock-out mice as well as mice that selectively express activating versus repressive forms of TCF-1 specifically in lymphocytes. We will use these newly generated tools to define the mechanisms by which Tim-3 determines anti-tumor immunity and the role of TCF-1 in this process. We propose the following specific aims: 1) Define the role of Tim-3 in CD4+FoxP3+ regulatory T cells; and 2) Define the role of Wnt signaling/TCF-1 in Tim-3-driven suppression of anti-tumor immunity.
描述(由申请人提供):T细胞抑制分子如CTLA-4、PD-1和Tim-3是T细胞应答的重要调节剂,已成为癌症中有价值的免疫靶点。在T细胞抑制分子中,Tim-3现在被认为是癌症中出现的功能失调或耗尽的CD 8 + T细胞的关键决定因素。事实上,我们是第一个表明Tim-3的表达特异性地标记肿瘤组织中存在的功能最失调或耗尽的CD 8 + T细胞群体,并且靶向Tim-3的免疫疗法显著改善靶向PD-1的免疫疗法的功效,以恢复耗尽的CD 8 + T细胞的功能并引发有效的抗肿瘤免疫。我们现在已经发现Tim-3的表达也标志着CD 4 + FoxP 3+调节性T细胞(Treg)的高度抑制性群体,其独特地存在于肿瘤组织中。我们的初步数据进一步表明Tim-3促进Treg的抑制功能。因此,Tim-3可以通过其在CD 8 + T细胞和Treg中的作用影响肿瘤免疫。然而,Tim-3如何在CD 8 + T细胞中发挥作用以抑制其反应,而在Treg中发挥作用以促进其抑制活性尚不清楚。我们现在发现TCF-1(T细胞因子1)在表现出功能失调表型的Tim-3+ CD 8+肿瘤浸润淋巴细胞(TILs)中特异性下调。我们的初步数据进一步显示,我们已经显示的Tim-3和PD-1信号传导的阻断消除了T细胞耗竭,恢复了Tim-3+ CD 8 + TIL中TCF-1的表达。我们进一步发现,TCF-1在Tim-3+ Treg中类似地下调,但在Tim-3- Treg中不下调,并且Tim-3/PD-1阻断恢复了Tim-3+ Treg中的TCF-1表达。TCF-1是经典Wnt信号通路中的关键转录因子。TCF-1是正常T细胞发育和长寿命中央记忆CD 8 + T细胞产生所需的,但Wnt信号传导和TCF-1在T细胞功能障碍/衰竭发展中的作用尚未得到解决。有趣的是,TCF-1最近已经涉及拮抗调节性T细胞功能,从而提高了TCF-1的Tim-3驱动的抑制是Tim-3+ Treg的有效抑制功能的基础的可能性。基于我们的初步数据,我们假设Tim-3通过涉及肿瘤内CD 8 + T细胞和Treg中Wnt信号传导和TCF-1的抑制的机制抑制抗肿瘤T细胞应答。我们处于独特的位置来剖析Tim-3和TCF-1在确定抗肿瘤T细胞应答中的作用,因为我们有可用的新工具,包括Tim- 3和TCF-1条件性敲除小鼠以及特异性地在淋巴细胞中选择性表达TCF-1的活化与抑制形式的小鼠。我们将使用这些新生成的工具来定义Tim-3决定抗肿瘤免疫的机制以及TCF-1在此过程中的作用。我们提出了以下具体目标:1)确定Tim-3在CD 4 + FoxP 3+调节性T细胞中的作用;和2)确定Wnt信号传导/TCF-1在Tim-3驱动的抗肿瘤免疫抑制中的作用。
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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ANA C ANDERSON其他文献
ANA C ANDERSON的其他文献
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