Immune Evasion by Nanog-Mediated Changes to the Tumor Microenvironment.

 描述(申请人提供)：越来越多的证据表明，肿瘤中干细胞状状态的出现和对宿主免疫防御的适应在很大程度上导致了癌症患者的疾病进展和复发。因此，重要的是要了解肿瘤获得干状状态并逃避免疫监视的机制，以降低癌症造成的死亡率。我们最近证实，通过免疫选择，癌细胞经历了一种主要的转录因子Nanog的上调，这是维持和自我更新多能干细胞的基础。Nanog的上调导致这些癌细胞的干细胞样和免疫耐药表型。因此，抑制Nanog使小鼠的肿瘤细胞容易受到CD8+细胞毒性T淋巴细胞(CTL)的杀伤。此外，我们还发现，Nanog在许多不同的人类癌症类型中都有丰富的表达，并且肿瘤组织中Nanog的表达上调与宫颈肿瘤患者的疾病分期和总生存期有关。到目前为止，我们的研究已经确定Nanog是癌症治疗的理想分子靶点，并表明癌症中的干细胞状态与免疫监测之间存在联系。本项目的主要目的是通过改变肿瘤微环境来研究Nanog在肿瘤免疫逃逸中的作用。我们假设，在宿主免疫监视的自然过程中，癌细胞朝着上调Nanog的方向发展，并且Nanog创造了一个保护肿瘤细胞免受CTL杀伤的微环境。具体地说，我们建议：(1)表征在肿瘤特异性免疫反应期间活动物中向上调Nanog表达的实时肿瘤进化；(2)表征Nanog在建立免疫抑制的肿瘤微环境中的作用；以及(3)表征Nanog介导免疫逃逸的分子机制。该项目的成功完成将为在宿主免疫系统的自然环境中调节肿瘤适应的机制提供实质性的洞察力。此外，它还将建立一个在分子水平上实时研究肿瘤进化的平台技术。此外，本项目还介绍并评估了干细胞样癌表型可能通过免疫监视和介导免疫逃逸而产生的概念。本研究结果将对肿瘤的治疗干预具有重要的临床意义。

 DESCRIPTION (provided by applicant): Accumulating evidence suggests that emergence of a stem-like state in the tumor and adaptation to host immune defenses are responsible in large part for disease progression and recurrence in cancer patients. Thus, it is important to understand the mechanisms through which the tumor acquires a stem-like condition and evades immune surveillance to reduce the mortality rate due to cancer. We recently demonstrated that through immune selection, cancer cells experience upregulation of Nanog, a master transcription factor, which is fundamental to the maintenance and self-renewal of pluripotent stem cells. Upregulation of Nanog results in a stem-like and immune-resistant phenotype of these cancer cells. Accordingly, inhibition of Nanog renders tumor cells susceptible to killing by CD8+ cytotoxic T lymphocytes (CTLs) in mice. Furthermore, we found that Nanog is abundant in many different human cancer types, and upregulation of Nanog in tumor tissue correlates with the disease stage and overall survival of patients with cervical neoplasia. Thus far, our studies have identified Nanog as an ideal molecular target for cancer therapy and suggest a link between the stem-like state in cancer and immune surveillance. The primary purpose of the current project is to investigate the role of Nanog in tumor immune escape through modification of the tumor microenvironment. We hypothesize that, in the natural course of host immune surveillance, cancer cells progress towards upregulation of Nanog and that Nanog creates a microenvironment that protects the tumor cells from killing by CTLs. Specifically, we propose to: (1) Characterize real-time tumor evolution towards upregulation of Nanog expression in live animals during a tumor-specific immune response; (2) Characterize the role of Nanog in the establishment of an immune- suppressive tumor microenvironment; and (3) Characterize the molecular mechanisms by which Nanog mediates immune escape. The successful completion of this project will provide substantial insight into the mechanisms that mediate tumor adaptation in the natural setting of the host immune system. Furthermore, it will establish a platform technology to investigate tumor evolution in real-time at the molecular level. Additionally, this project introduces and evaluates the concept that the stem-like phenotype of cancer may arise through immune surveillance and mediate immune escape. The results of this study will have significant clinical implications for the therapeutic intervention of cancer.