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 是我们实验室发现的一种在终末分化 IFN-�- 上特异性表达的分子 我们的初步工作表明，Tim-3 是诱导抗原所必需的。 特异性耐受性，并且使用可溶性 Tim-3-Ig 融合物阻断 Tim-3 会加剧自身免疫。 蛋白质，我们鉴定了两种与 Tim-3 结合的分子种类，其中之一被解析为 Galectin-9（Gal- 9). 然后我们证明 Gal-9 触发 Tim-3 会诱导 IFN-β 分泌细胞死亡。 我们提出 Tim-3 是一种抑制分子，可以抑制由 IFN-驱动的炎症。- 我们小组和其他人的最新研究将 Tim-3 的抑制作用扩展到了 T 细胞。 慢性病毒感染和癌症中出现的功能失调/耗尽的 CD8+ T 细胞。 Tim-3 信号可恢复耗尽的 T 细胞的功能并改善临床结果。 Tim-3 也在高度抑制的 FoxP3+ 调节性 T 细胞 (Treg) 群体中表达，这些细胞 在荷瘤宿主的肿瘤组织中独特发现的，很大程度上基于这些数据，针对的治疗。 考虑到这些因素，Tim-3 目前正在为癌症患者开发，令人惊讶的是其含量如此之少。 已知驱动 Tim-3 表达的信号以及 Tim-3 如何介导其抑制功能。 解决这些问题对于临床开发能够成功靶向的疗法至关重要 Tim-3用于治疗人类疾病。 我们现在已经确定 IL-27 是驱动 Tim-3 表达的关键细胞因子，并且在细胞中缺乏 IL-27 信号 体内导致 CD8+ 肿瘤浸润淋巴细胞 (TIL) 上 Tim-3 的表达缺陷，改善效应细胞 我们进一步有了新的发现： 癌胚抗原相关细胞粘附分子-1 (CEACAM-1) 是一种新型 Tim-3 配体，可结合 Tim-3 顺式调节 TIM-3 表达，反式诱导 TIM-3 介导的抑制信号。 根据我们的初步数据，我们发现 IL-27 通过驱动 Tim-3 抑制抗肿瘤免疫力 和 CEACAM-1 表达抑制 CD8+ 效应 T 细胞反应并促进 Treg 驱动 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。 具体目标如下： 1) 确定IL-27驱动T细胞耗竭并抑制抗肿瘤免疫的机制。 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在调节癌症中Tim-3功能中的作用。