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

 描述（由申请人提供）：越来越多的证据表明，肿瘤中干细胞样状态的出现和对宿主免疫防御的适应在很大程度上是癌症患者疾病进展和复发的原因。因此，重要的是要了解肿瘤获得干细胞样状态并逃避免疫监视以降低癌症死亡率的机制。我们最近证明，通过免疫选择，癌细胞经历Nanog的上调，Nanog是一种主转录因子，这是多能干细胞维持和自我更新的基础。Nanog的上调导致这些癌细胞的干细胞样和免疫抗性表型。因此，Nanog的抑制使得肿瘤细胞易于被小鼠中的CD 8+细胞毒性T淋巴细胞（CTL）杀死。此外，我们发现Nanog在许多不同的人类癌症类型中含量丰富，肿瘤组织中Nanog的上调与宫颈肿瘤患者的疾病分期和总生存率相关。到目前为止，我们的研究已经将Nanog确定为癌症治疗的理想分子靶点，并表明癌症中的干细胞样状态与免疫监视之间存在联系。本项目的主要目的是通过修饰肿瘤微环境来研究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Nanog上调的方向发展，Nanog创造了一个保护肿瘤细胞免受CTL杀伤的微环境。具体而言，我们建议：（1）表征肿瘤特异性免疫应答期间活体动物中Nanog表达上调的实时肿瘤演变;（2）表征Nanog在建立免疫抑制性肿瘤微环境中的作用;和（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介导肿瘤适应的机制提供实质性的见解。此外，它将建立一个平台技术，在分子水平上实时研究肿瘤的演变。此外，该项目还介绍和评估了癌症的干细胞样表型可能通过免疫监视和介导免疫逃逸而产生的概念。本研究的结果将对癌症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.