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（由申请人提供）：T 细胞抑制分子如 CTLA-4、PD-1 和 Tim-3 是 T 细胞反应的重要调节剂，已成为癌症中有价值的免疫治疗靶点。在 T 细胞抑制分子中，Tim-3 现在被认为是癌症中出现功能障碍或耗尽的 CD8+ T 细胞的关键决定因素。事实上，我们首次证明 Tim-3 的表达特异性地标记了肿瘤组织中存在的最功能失调或衰竭的 CD8+ T 细胞群，并且针对 Tim-3 的免疫疗法显着提高了针对 PD-1 的免疫疗法的疗效，以恢复衰竭的 CD8+ T 细胞的功能并引发有效的抗肿瘤免疫。我们现在发现 Tim-3 的表达还标志着肿瘤组织中独特存在的 CD4+ FoxP3+ 调节性 T 细胞 (Treg) 的高度抑制群体。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 可以通过其对 CD8+ T 细胞和 Treg 的作用影响肿瘤免疫。然而，Tim-3 如何在 CD8+ T 细胞中发挥作用以抑制其反应，而在 Treg 中如何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+ CD8+ 肿瘤浸润淋巴细胞 (TIL) 中特异性下调。我们的初步数据进一步表明，阻断 Tim-3 和 PD-1 信号传导可以消除 T 细胞耗竭，恢复 Tim-3+ CD8+ TIL 中 TCF-1 的表达。我们进一步发现 TCF-1 在 Tim-3+ 中类似地下调，但 Tim-3- Treg 中没有，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 CD8+ T 细胞生成所必需的，但 Wnt 信号传导和 TCF-1 在 T 细胞功能障碍/耗竭发展中的作用尚未得到解决。有趣的是，TCF-1 最近被认为参与拮抗调节性 T 细胞功能，因此提出了 Tim-3 驱动的 TCF-1 抑制是 Tim-3+ Treg 有效抑制功能的基础的可能性。根据我们的初步数据，我们假设 Tim-3 通过抑制肿瘤内 CD8+ T 细胞和 Treg 中的 Wnt 信号传导和 TCF-1 的机制来抑制抗肿瘤 T 细胞反应。我们处于一个独特的位置，可以剖析 Tim-3 和 TCF-1 在确定抗肿瘤 T 细胞反应中的作用，因为我们拥有可用的新工具，包括 Tim-3 和 TCF-1 条件敲除小鼠以及在淋巴细胞中选择性表达 TCF-1 激活或抑制形式的小鼠。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。我们提出以下具体目标：1）明确Tim-3在CD4+FoxP3+调节性T细胞中的作用； 2) 定义 Wnt 信号/TCF-1 在 Tim-3 驱动的抗肿瘤免疫抑制中的作用。