Role of IRF8 in Tumor Rejection and Suppression

IRF8 在肿瘤排斥和抑制中的作用

• 批准号: 8962673
• 负责人: KEBIN LIU
• 金额: $ 30.78万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962673
• 关键词: Allografting; Antigens; Apoptosis; Apoptotic; CD8B1 gene; Cancer Patient; Cell Differentiation process; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Structure; Colon; Colon Carcinoma; Colorectal Cancer; Cytotoxic T-Lymphocytes; DNA; DNA Methylation; Development; Disease; Dose; Exhibits; Funding; Generations; Genes; Genetic Transcription; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Histones; Human; Immune; Immune system; Immunologic Surveillance; In Vitro; Inhibitory Concentration 50; Investigation; Knockout Mice; Legal patent; Link; Lymphocyte Activation; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular; Molecular Target; Mus; Myelogenous; Myeloid Cells; Nature; Neoplasm Metastasis; Paper; Pathogenesis; Peer Review; Play; Promoter Regions; Proteins; Publishing; Recruitment Activity; Recurrence; Regulation; Research; Research Project Grants; Resistance; Role; Suppressor-Effector T-Lymphocytes; T cell differentiation; T-Lymphocyte; Testing; Tissues; Transcriptional Activation; Transcriptional Regulation; Tumor Antigens; Tumor Suppressor Proteins; Universities; Vaccination; cancer cell; cancer immunotherapy; cancer therapy; colon cancer patients; genome-wide; histone methyltransferase; in vivo; inhibitor/antagonist; metastatic colorectal; neoplastic cell; outcome forecast; promoter; public health relevance; receptor; response; tumor; tumor microenvironment; verticillin A

 DESCRIPTION (provided by applicant): Metastasis represents the single most significant challenge in human colorectal cancer (CRC) treatment. FasL-mediated immune surveillance by T cells is essential for the control of spontaneous cancer growth and metastasis. However, acquisition of resistance to FasL-induced apoptosis is a hallmark of human cancer, particularly metastatic human cancer. In humans, the Fas protein level is high in normal colon tissues, but is generally lower in the primary CRC, and complete loss of Fas protein is often observed in metastatic CRC. Furthermore, it has been shown that acquisition of resistance to Fas-mediated apoptosis is linked to recurrence and adverse prognosis in human CRC patients. Therefore, targeting resistance to Fas-mediated apoptosis is potentially an effective approach to overcome metastatic CRC resistance to FasL+ cytotoxic T lymphocyte (CTL) to suppress CRC immune evasion and progression. On the other hand, IRF8 plays an essential role in: 1) Fas transcription in tumor cells, 2) suppression of MDSC differentiation, and 3) regulation of CTL differentiation. Cancer is not a disease of tumor cell alone, but rather a disease of the tumor microenvironment, which consists of both tumor cells and immune cells. Therefore, systemic investigation of IRF8 functions in regulation of Fas and GM-CSF expression in tumor cells, and regulation MDSC differentiation and CTL differentiation of the immune system is of significance for understanding the cancer pathogenesis in the immune competent hosts. Our central hypothesis is that H3K9me3-mediated FAS transcriptional silencing is a molecular mechanism underlying metastatic colon carcinoma cell immune evasion and IRF8 functions in host tumor rejection through regulating MDSC and CTL differentiation. We propose to test our central hypothesis by pursuing the following 3 specific aims: 1. test the hypothesis that H3K9me3 interferes with interaction between IRF8 and the FAS promoter to represses FAS transcription in metastatic human colon carcinoma cells; 2. test the hypothesis that IRF8 represses GM-CSF expression in tumor cells to mediate tumor-induced MDSC differentiation in vivo; 3. determine the functions of IRF8 in host immune cell-mediated tumor rejection. Successful completion of these proposed studies has the potential to identify molecular targets to enhance the efficacy of CTL cancer immunotherapy to suppress metastatic colorectal cancer.

 描述（由申请人提供）：转移是人类结直肠癌（CRC）治疗中最重要的挑战。FasL介导的T细胞免疫监视对于控制自发性癌症生长和转移是必不可少的。然而，获得对FasL诱导的细胞凋亡的抗性是人类癌症，特别是转移性人类癌症的标志。在人类中，Fas蛋白水平在正常结肠组织中较高，但在原发性CRC中通常较低，并且在转移性CRC中经常观察到Fas蛋白的完全丧失。此外，已经表明，获得对Fas介导的细胞凋亡的抗性与人CRC患者的复发和不良预后有关。因此，靶向抵抗Fas介导的细胞凋亡可能是克服转移性CRC对FasL+细胞毒性T淋巴细胞（CTL）的抵抗以抑制CRC免疫逃避和进展的有效方法。另一方面，IRF 8在以下方面起重要作用：1）肿瘤细胞中Fas的转录，2）MDSC分化的抑制，和3）CTL分化的调节。癌症不仅仅是肿瘤细胞的疾病，而是由肿瘤细胞和免疫细胞组成的肿瘤微环境的疾病。因此，系统研究IRF 8对肿瘤细胞Fas和GM-CSF表达的调控，以及对免疫系统MDSC分化和CTL分化的调控，对于了解免疫活性宿主的肿瘤发病机制具有重要意义。我们的中心假设是，H3 K9 me 3介导的FAS转录沉默是转移性结肠癌细胞免疫逃避和IRF 8通过调节MDSC和CTL分化在宿主肿瘤排斥中发挥功能的分子机制。我们建议通过追求以下3个具体目标来测试我们的中心假设：1。检验H3 K9 me 3干扰IRF 8和FAS启动子之间的相互作用以抑制转移性人结肠癌细胞中FAS转录的假设; 2.检验IRF 8抑制肿瘤细胞中GM-CSF表达以介导肿瘤诱导的MDSC体内分化的假设; 3.确定IRF 8在宿主免疫细胞介导的肿瘤排斥中的功能。成功完成这些拟议的研究有可能确定分子靶点，以提高CTL癌症免疫疗法抑制转移性结直肠癌的疗效。