Generation and analysis of immunity inside tumor tissues

肿瘤组织内免疫的产生和分析

• 批准号: 7356444
• 负责人: Ping Yu
• 金额: $ 9.66万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356444
• 关键词: Activated Lymphocyte; Address; Adoptive Transfer; Bread; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Model; Cancerous; Cell Proliferation; Cell physiology; Cells; Clinical; Condition; Coupled; Data; Disease; Disease model; Disease regression; Distal; Environment; Event; Generations; Goals; Hematopoietic; Herpesviridae; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Language; Lead; Light; Lymphoid; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Natural Killer Cells; Neoplasm Metastasis; Outcome; Pathway interactions; Personal Satisfaction; Phenotype; Pilot Projects; Play; Population; Prevention; Principal Investigator; Recruitment Activity; Regulation; Regulatory Pathway; Research; Research Personnel; Role; Safety; Signal Transduction; Site; Stromal Cells; Structure; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Transgenic Mice; Tumor Antigens; Tumor Expansion; Tumor Immunity; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Tissue; cancer regression; cancer therapy; clinically relevant; human TNF protein; in vivo; member; migration; mortality; mouse model; neoplastic cell; prevent; programs; receptor; response; trafficking; tumor; vector

DESCRIPTION (provided by applicant): Dr. Yu's long term goal is to understand how the immune system responds to syngeneic cancerous cells and tissues, and how stronger immune responses can be promoted against the malignancies. The current application is intended to uncover the mechanisms of how LIGHT, a newly-identified tumor necrosis factor superfamily (TNFSF) member, induces a strong anti-tumor immunity and test the application of LIGHT to tumor immunotherapy in a clinically relevant setting. We know that LIGHT can induce an immune-mediated tumor rejection, however, the mechanisms of how LIGHT provokes such a strong anti-tumor immunity has not been well studied. We strongly believe that LIGHT is a good candidate for tumor immunotherapy in spontaneous metastatic disease, but its full potential has yet to be determined. Our preliminary data suggests that LIGHT can not only attract and stimulate tumor-specific CD8+ T cells, but also regulate NK and CD4+ regulatory T cells. Moreover, our pilot study demonstrates that the utilization of an adeno-LIGHT vector can indeed treat spontaneous metastases in a mouse model. We propose that LIGHT, unlike many other co-stimulatory molecules, has the advantage to regulate both the stromal and hematopoietic immune pathways via its receptors, LT? receptor (LT?R) and Herpes Virus Entry Mediator (HVEM). Specifically, these goals will be pursued with the following three specific aims: Aim 1: To investigate how LIGHT-mediated tumor environment promotes NK function in eliciting tumor rejection and define the roles of NK cells in anti-tumor immunity. Aim 2: Define the role of LIGHT in regulation of CD4+ suppressive T cells inside the tumor. Aim 3: Define the role of LIGHT in promoting immune recognition in spontaneous metastatic tumor models. The expected results from this research will define the mechanisms by which LIGHT mediates anti-tumor immunity and determine ways of delivering LIGHT into the tumor tissue that would be clinically relevant. This study will also elucidate if LIGHT can be utilized as a potential therapeutic agent for treating metastatic disease. Lay language: Despite evidence of tumor antigens that can be recognized by immune system, spontaneous regression of cancers rarely occurs. A molecule LIGHT, expressed on tumors, can induce a rapid tumor regression. This application intends to explore the mechanisms involved as well as develop clinically relevant cancer therapy with LIGHT.

描述（由申请人提供）：Yu博士的长期目标是了解免疫系统如何对同质癌细胞和组织作出反应，以及如何促进更强的免疫反应来对抗恶性肿瘤。目前的申请旨在揭示新发现的肿瘤坏死因子超家族（TNFSF）成员LIGHT诱导强抗肿瘤免疫的机制，并在临床相关环境中测试LIGHT在肿瘤免疫治疗中的应用。我们知道LIGHT可以诱导免疫介导的肿瘤排斥反应，然而，LIGHT如何激发如此强大的抗肿瘤免疫的机制尚未得到很好的研究。我们坚信LIGHT是自发转移性肿瘤免疫治疗的良好候选药物，但其全部潜力尚未确定。我们的初步数据表明，LIGHT不仅可以吸引和刺激肿瘤特异性CD8+ T细胞，还可以调节NK和CD4+调节性T细胞。此外，我们的初步研究表明，利用腺光载体确实可以治疗小鼠模型中的自发转移。我们认为，与许多其他共刺激分子不同，LIGHT具有通过其受体调节基质和造血免疫途径的优势。受体(LT吗?R)和疱疹病毒进入介质（HVEM）。具体来说，这些目标将通过以下三个具体目标来实现：目的1：研究光介导的肿瘤环境如何促进NK细胞在引发肿瘤排斥反应中的功能，并确定NK细胞在抗肿瘤免疫中的作用。目的2：明确LIGHT在调节肿瘤内CD4+抑制性T细胞中的作用。目的3：明确在自发转移性肿瘤模型中，LIGHT在促进免疫识别中的作用。这项研究的预期结果将确定LIGHT介导抗肿瘤免疫的机制，并确定将LIGHT输送到肿瘤组织的方法，这将具有临床意义。这项研究还将阐明LIGHT是否可以作为治疗转移性疾病的潜在治疗剂。外话：尽管有证据表明肿瘤抗原可以被免疫系统识别，但癌症的自发消退很少发生。在肿瘤上表达的一种分子LIGHT可以诱导肿瘤快速消退。本申请旨在探索其相关机制，并利用LIGHT开发临床相关的癌症治疗。