Role of IRF8 in Tumor Rejection and Suppression

 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。T细胞通过FasL介导的免疫监视对于控制自发性肿瘤的生长和转移是必不可少的。然而，获得对FasL诱导的细胞凋亡的抵抗是人类癌症，特别是转移性人类癌症的一个标志。在人类正常结肠组织中Fas蛋白表达水平较高，而在原发结直肠癌组织中Fas蛋白表达水平普遍较低，转移性结直肠癌组织中Fas蛋白表达常完全缺失。此外，已有研究表明，获得对Fas介导的细胞凋亡的抵抗与人类结直肠癌患者的复发和不良预后有关。因此，靶向Fas介导的细胞凋亡抵抗是克服转移性结直肠癌对FasL+细胞毒性T淋巴细胞(CTL)耐药的一种潜在的有效方法，从而抑制结直肠癌免疫逃避和进展。另一方面，IRF8在肿瘤细胞Fas转录、抑制MDSC分化、调节CTL分化等方面发挥重要作用。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共同作用的肿瘤微环境的疾病。因此，系统研究IRF8在调节肿瘤细胞Fas和GM-CSF表达中的作用，调控免疫系统的MDSC分化和CTL分化，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H3K9me3介导的Fas转录沉默是转移性结肠癌细胞免疫逃避的分子机制，而IRF8通过调节MDSC和CTL分化而在宿主肿瘤排斥反应中发挥作用。我们打算通过追求以下三个特定目标来验证我们的中心假说：1.检验H3K9me3干扰IRF8和Fas启动子之间的相互作用以抑制转移性人结肠癌细胞Fas转录的假说；2.检验IRF8抑制肿瘤细胞中GM-CSF表达以介导体内肿瘤诱导的MDSC分化的假说；3.确定IRF8在宿主免疫细胞介导的肿瘤排斥反应中的作用。这些拟议研究的成功完成有可能确定分子靶点，以增强CTL癌症免疫疗法抑制转移性结直肠癌的疗效。

 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.