Molecular mechanism by which Tim-3 induces T cell dysfunction and inhibits anti-t

Tim-3诱导T细胞功能障碍并抑制抗t细胞的分子机制

• 批准号: 8794861
• 负责人: VIJAY K. KUCHROO
• 金额: $ 32.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8794861
• 关键词: Address; Antigen-Presenting Cells; Antigens; Autoimmunity; Automobile Driving; Binding; CD8B1 gene; Cancer Patient; Cell Adhesion Molecules; Cell Death; Cell physiology; Cells; Chimeric Proteins; Chronic; Chronic Disease; Clinical; Collaborations; Contracts; Data; Development; Functional disorder; Galactose Binding Lectin; Gene Expression Regulation; Gene Family; Generations; Genes; Health; ITIM; Immunity; In Vitro; Inflammation; Interferons; Interleukin-12; Investigation; Laboratories; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Molecular; Outcome; Phenotype; Population; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Tumor Immunity; Tumor Tissue; Tumor-Infiltrating Lymphocytes; United States; Viral; Viral Cancer; Virus Diseases; Work; abstracting; base; cytokine; cytotoxic; exhaust; exhaustion; functional restoration; human disease; immune function; improved; in vivo; novel; programs; targeted treatment; therapy development; transcription factor; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY/ABSTRACT - PROJECT 1 Tim-3 was discovered in our laboratory as a molecule specifically expressed on terminally differentiated IFN-�- secreting CD4+ and CD8+ T cells. Our initial work showed that Tim-3 is required for the induction of antigen- specific tolerance and that blockade of Tim-3 exacerbates autoimmunity. Using a soluble Tim-3-Ig-fusion protein, we identified two molecular species that bind to Tim-3, one of which was resolved as Galectin-9 (Gal- 9). We then showed that Gal-9-triggering of Tim-3 induces cell death in IFN-�-secreting cells. These data led us to propose that Tim-3 is an inhibitory molecule that serves to contract inflammation driven by IFN-�- secreting T cells. Recent research from our group and others has extended the inhibitory role of Tim-3 to the dysfunctional/exhausted CD8+ T cells that arise in chronic viral infections and cancer. Importantly, blockade of Tim-3 signals restores function to exhausted T cells and improves clinical outcome. We have now identified that Tim-3 is also expressed on a highly suppressive population of FoxP3+ regulatory T cells (Treg) that are uniquely found in the tumor tissue of tumor-bearing hosts. Largely based on these data, therapies that target Tim-3 are currently being developed for cancer patients. Given these considerations, it is surprising how little is known regarding the signals that drive Tim-3 expression and how Tim-3 mediates its inhibitory function. Addressing these issues is critical to inform the clinical development of therapies that could successfully target Tim-3 for the treatment of human disease. We have now identified IL-27 as a key cytokine that drives Tim-3 expression and that lack of IL-27 signaling in vivo results in defective expression of Tim-3 on CD8+ tumor infiltrating lymphocytes (TILs), improved effector function in CD8+ T cells, and enhanced anti-tumor immunity. We have further made the novel discovery that carcinoembyronic antigen-related cell adhesion molecule-1 (CEACAM-1), is a novel Tim-3 ligand that binds to Tim-3 in cis to regulate TIM-3 expression and in trans to induce TIM-3 mediated inhibitory signals. Based on our preliminary data, we hypothesize that IL-27 dampens anti-tumor immunity by driving Tim-3 and CEACAM-1 expression to suppress CD8+ effector T cell responses and promote Treg-driven regulation of T cell responses in the tumor microenvironment. To address this hypothesis, we propose the following specific aims: 1) Determine the mechanism by which IL-27 drives T cell exhaustion and suppresses anti-tumor immunity. 2) Determine the regulation of the gene signature of Tim-3+ CD8+ T cells in cancer. 3) Determine the role of CEACAM-1 in regulating Tim-3 function in cancer.

项目摘要/摘要 - 项目1 TIM-3在我们的实验室中发现是在终端分化的IFN--------- 分泌CD4+和CD8+ T细胞。我们最初的工作表明，诱导抗原需要TIM-3是必需的 特定的公差和TIM-3的阻滞加剧了自身免疫性。使用可溶性tim-3-ig融合 蛋白质，我们鉴定了两个与TIM-3结合的分子物种，其中一种被解析为Galectin-9（GAL- 9）。然后，我们证明了TIM-3的GAL-9触发诱导IFN-分泌细胞中的细胞死亡。这些数据引导 我们建议Tim-3是一种抑制性分子，用于由IFN--------- 分泌T细胞。我们小组和其他人的最新研究扩大了TIM-3的抑制作用 在慢性病毒感染和癌症中出现的功能失调/耗尽的CD8+ T细胞。重要的是，块 TIM-3信号恢复了耗尽的T细胞的功能并改善临床结果。我们现在已经确定了 TIM-3也以高度抑制的FOXP3+调节性T细胞（Treg）表示 在肿瘤宿主的肿瘤组织中独特发现。在很大程度上基于这些数据，靶向的疗法 TIM-3目前正在为癌症患者开发。考虑到这些考虑，令人惊讶的是很少 知道驱动TIM-3表达以及TIM-3如何培养其抑制功能的信号。 解决这些问题至关重要，对于可以成功针对的疗法的临床发展至关重要 TIM-3用于治疗人类疾病。 现在，我们已经确定IL-27是驱动TIM-3表达的关键细胞因子，并且缺乏IL-27信号传导 体内导致TIM-3在CD8+肿瘤浸润淋巴细胞（TILS）上的表达有缺陷，改善了效应子 在CD8+ T细胞中起作用，并增强了抗肿瘤免疫力。我们进一步发现了小说发现 癌甲辅发抗原相关的细胞粘附分子-1（CEACAM-1）是一种新型TIM-3配体，与结合 CI中的TIM-3调节TIM-3表达和反式诱导TIM-3介导的抑制信号。 根据我们的初步数据，我们假设IL-27通过驱动TIM-3来抑制抗肿瘤免疫力 和CEACAM-1表达以抑制CD8+效应T细胞反应并促进Treg驱动 调节肿瘤微环境中T细胞反应的调节。为了解决这一假设，我们提出了 以下具体目的： 1）确定IL-27驱动T细胞耗尽并抑制抗肿瘤免疫力的机制。 2）确定癌症中TIM-3+ CD8+ T细胞的基因特征的调节。 3）确定CEACAM-1在控制TIM-3功能在癌症中的作用。