The regulation of dendritic cell function by LMYC at steady state and during immune responses to cancer

LMYC 在稳态和癌症免疫反应过程中对树突状细胞功能的调节

• 批准号: 9900755
• 负责人: David Alexander Anderson
• 金额: $ 3.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900755
• 关键词: Activated Lymphocyte; Acute Lymphocytic Leukemia; Antigens; Antitumor Response; Autoantigens; Biochemical; Biological Assay; Biological Process; CD8-Positive T-Lymphocytes; Cancer Model; Cell Lineage; Cell physiology; Defect; Dendritic Cells; Dependence; Development; Disseminated Malignant Neoplasm; Embryonic Development; Family; Family member; Genes; Genetic Transcription; Hematopoiesis; Hodgkin Disease; Homeostasis; Human; Immune; Immune response; Immune system; Immunotherapy; Impairment; In Vitro; Infection; Knock-in; Knockout Mice; MYCL1 gene; MYCN gene; Malignant Neoplasms; Mediating; Metabolic; Modeling; Molecular; Molecular Target; Mus; Oncogenes; Outcome; Pathway interactions; Phenotype; Physiology; Process; Protein Biosynthesis; Regulation; Reporter; Reporting; Research; Respiration; Role; Testing; Therapeutic; Tumor Antigens; Tumor Immunity; Work; adaptive immune response; anti-tumor immune response; cancer cell; cancer immunotherapy; cell transformation; fighting; immune checkpoint blockade; immunogenic; immunoregulation; improved; in vivo; in vivo Model; leukemia/lymphoma; melanoma; molecular marker; mouse model; neoplasm immunotherapy; novel; novel therapeutics; pathogen; patient response; rapid growth; response; transcription factor; transcriptome; tumor; tumor microenvironment; tumorigenesis

Project Summary It is estimated that nearly 1.5 million new cases of cancer are reported each year. Until recently, treatment options for metastatic cancers have been limited. However, therapies that harness the activity of the host immune system have proven successful in the treatment of recalcitrant cancers such as melanoma, acute lymphoblastic leukemia and Hodgkin lymphoma. Numerous immune cell lineages regulate anti-tumor responses, including Batf3-dependent dendritic cells, which cross-present antigens to naïve CD8 T cells and initiate adaptive immune responses against cancer cells. Therefore, research to identify the factors that regulate the development and function of dendritic cells can advance our understanding of immune responses to cancer and reveal putative molecular targets for cancer immunotherapy. The present proposal aims to define the mechanism by which the transcription factor, LMYC, regulates DC function and in turn whether LMYC is required for steady state and immunotherapy-induced tumor rejection. We have generated Mycl1-GFP knockin/knockout mice that serve as in vivo reporters of Mycl1 expression and Mycl1-deficiency. Using this model, we have shown previously that Mycl1 is required for optimal priming of naïve CD8 T cells during infections. Given that both CD8 T cells and Batf3-dependent dendritic cells are required for tumor rejection and positive responses to immunotherapy, we hypothesize that Mycl1 is required for these processes. In Aim1, we will define the molecular mechanism by which LMYC supports the core function of Batf3-dependent dendritic cells. We will first determine the impact of LMYC deficiency on global transcription to identify pathways that are dysregulated at steady state. In vivo and in vitro biochemical analyses will be employed to validate that broad defects in transcription result in downstream effects on core biological processes, such as protein synthesis and respiration, which are broadly regulated by MYC family members. In Aim2, we will determine whether steady state and immunotherapy-induced rejection of immunogenic tumors is dependent on intrinsic expression of Mycl1 by Batf3-dependent dendritic cells. Simultaneously, we will analyze the impact of the tumor microenvironment and immunotherapies on the expression of Mycl1 by dendritic cells in vivo. If Mycl1 expression correlates with rejection outcomes in a mouse model of checkpoint blockade, it may serve as a molecular biomarker to predict patient responses to cancer immunotherapy. Therefore, the results of this study will advance our understanding of the molecular mechanisms that control dendritic cell function as well as the molecules required for steady state and immunotherapy-induced immune responses to cancer.

项目摘要 据估计，每年有近150万新的癌症病例报告。直到最近， 转移性癌症的治疗选择有限。然而，利用细胞活性的疗法， 宿主免疫系统已被证明在治疗恶性肿瘤如黑素瘤、急性 淋巴母细胞白血病和霍奇金淋巴瘤。许多免疫细胞谱系调节抗肿瘤 免疫应答，包括Batf 3依赖性树突状细胞，其交叉呈递抗原至幼稚CD 8 T细胞， 启动针对癌细胞的适应性免疫反应。因此，研究确定的因素， 调节树突状细胞的发育和功能可以促进我们对免疫反应的理解 并揭示癌症免疫治疗的假定分子靶点。 目前的建议旨在确定转录因子LMYC调节的机制， DC功能以及LMYC是否是稳态和免疫疗法诱导的肿瘤所需的 排斥反应我们已经产生了Mycl 1-GFP敲入/敲除小鼠，作为Mycl 1的体内报告基因 表达和Mycl 1缺陷。使用这个模型，我们之前已经证明，Mycl 1是必需的， 在感染期间初始CD 8 T细胞的最佳引发。考虑到CD 8 T细胞和Batf 3依赖性T细胞两者都可以被激活。 树突状细胞是肿瘤排斥和免疫治疗阳性反应所必需的，我们假设， Mycl 1是这些过程所必需的。在Aim 1中，我们将定义LMYC的分子机制， 支持Batf 3依赖性树突细胞的核心功能。我们将首先确定LMYC的影响 在整体转录上的缺陷，以确定在稳态失调的途径。体内和体外 将采用生物化学分析来验证转录中的广泛缺陷导致下游转录。 对核心生物过程的影响，如蛋白质合成和呼吸，这些过程受到广泛的调节， MYC家族成员在Aim 2中，我们将确定稳态和免疫治疗诱导的排斥反应是否 免疫原性肿瘤的发生依赖于Batf 3依赖性树突状细胞内在表达Mycl 1。 同时，我们将分析肿瘤微环境和免疫治疗对肿瘤细胞增殖的影响。 树突状细胞体内Mycl 1的表达。如果Mycl 1表达与排斥反应结果相关， 检查点阻断的小鼠模型，它可以作为一种分子生物标志物来预测患者对 癌症免疫疗法因此，这项研究的结果将促进我们对分子生物学的理解。 控制树突状细胞功能的机制以及稳态所需的分子， 免疫疗法诱导的对癌症的免疫应答。