Role of Tim-3 in determining T cell immunity

Tim-3 在决定 T 细胞免疫中的作用

• 批准号: 9210064
• 负责人: ANA C ANDERSON
• 金额: $ 37.77万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9210064
• 关键词: Address; Affect; Agonist; Alpha Cell; Antibodies; Automobile Driving; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cell physiology; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Development; Exhibits; FOXP3 gene; Functional disorder; Generations; Human; Immune system; Immunity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Knockout Mice; Knowledge; Laboratories; Lymphocyte; Malignant Neoplasms; Memory; Morbidity - disease rate; Mus; Pathway interactions; Phenotype; Population; Positioning Attribute; Pre-Clinical Model; Process; Regulatory T-Lymphocyte; Repression; Role; Signal Transduction; T cell response; T cell transcription factor 1; T-Cell Development; T-Lymphocyte; Tissues; Tumor Immunity; Tumor Tissue; Tumor-Infiltrating Lymphocytes; WNT Signaling Pathway; advanced disease; base; exhaust; exhaustion; fighting; functional restoration; improved; mortality; novel; overexpression; public health relevance; receptor; response; selective expression; tool; transcription factor; tumor; tumor growth

 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（由适用提供）：T细胞抑制分子（例如CTLA-4，PD-1和TIM-3）是T细胞反应的重要调节剂，它已成为癌症中有价值的免疫治疗靶标。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CD8+ T细胞的关键决定剂。的确，我们是第一个表明TIM-3表达的人，特异性标志着肿瘤组织中存在的CD8+ T细胞的功能失调或耗尽的人群，靶向TIM-3的免疫疗法显着提高了免疫疗法的效率，该免疫疗法靶向PD-1的PD-1效率，用于恢复耗尽CD8+ T细胞的功能，以使CD8+ Telliment antiment tostiment Tostictiment Tostimitive潜在的潜在的抗潜在的免疫免疫原子化的效果。现在，我们发现TIM-3的表达还标志着在肿瘤组织中独特地存在的CD4+ FOXP3+调节性T细胞（Treg）的高度抑制。我们的初步数据进一步表明TIM-3促进了Treg的抑制功能。这是TIM-3可以通过其在CD8+ T细胞和Treg中的作用来影响肿瘤免疫学。但是，尚不清楚TIM-3在Treg功能中如何在CD8+ T细胞中发挥作用，以促进其抑制活性。现在，我们发现在暴露于暴露于功能障碍表型的TIM-3+ CD8+肿瘤浸润淋巴细胞（TILS）中，TCF-1（T细胞因子1）在TIM-3+ CD8+肿瘤浸润淋巴细胞（TILS）中被特异性下调。我们的初步数据进一步表明，我们已经显示的TIM-3和PD-1信号传导的封锁消除了T细胞耗尽，它恢复了TCF-1在TIM-3+ CD8+ TIL中的表达。我们进一步发现，TCF-1在TIM-3+中类似地下调，但不是Tim-3- Treg，而TIM-3/PD-1阻断恢复了Tim-3+ Treg中的TCF-1表达。 TCF-1是规范Wnt信号通路中的关键转录因子。 TCF-1是正常T细胞发育所必需的，并且生成长寿命的中央记忆CD8+ T细胞需要WNT信号传导和TCF-1在T细胞功能障碍/精疲力尽中的作用。有趣的是，最近在拮抗调节性T细胞功能中暗示了TCF-1，从而增加了TCF-1的TIM-3-DRIVN表示的可能性，这是TIM-3+ Treg的有效抑制功能的基础。根据我们的初步数据，我们假设TIM-3通过一种机制抑制抗肿瘤T细胞反应，该机制涉及Wnt信号传导和TCF-1在肿瘤内CD8+ T细胞和Treg中的表达。我们处于独特的位置，可以剖析TIM-3和TCF-1在确定抗肿瘤T细胞响应中的作用，因为我们具有可用的新颖工具，包括TIM-3和TCF-1条件敲除小鼠以及在淋巴细胞中特异性地表达激活与反射性TCF-1的反射形式的小鼠。我们将使用这些新生成的工具来定义TIM-3确定抗肿瘤免疫力以及TCF-1在此过程中的作用的机制。我们提出以下特定目的：1）定义TIM-3在CD4+ FOXP3+调节性T细胞中的作用； 2）定义Wnt信号传导/TCF-1在TIM-3驱动的抗肿瘤免疫抑制中的作用。