Nanog as a gateway to the immune-suppressive state in cancer

描述(申请人提供)：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癌症患者的疾病进展和复发。因此，为了降低癌症的死亡率，重要的是了解肿瘤获得干状状态和逃避免疫监视的方式。我们最近发现，在免疫选择过程中，癌细胞获得了Nanog的表达，Nanog是一种在多能干细胞维持和自我更新中起关键作用的主要转录因子。Nanog赋予这些癌细胞干细胞样和免疫耐受的表型，抑制Nanog可以通过CD8+细胞毒性T淋巴细胞(CTL)在小鼠体内消除肿瘤。此外，我们还发现，Nanog在多种人类癌症类型中都有丰富的表达，并且在肿瘤组织中的表达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是癌症治疗的主要分子靶点，并表明癌症中的干状状态与免疫监测之间存在联系。本项目的目的是研究Nanog在肿瘤免疫逃逸中的作用。我们假设癌细胞在宿主免疫监视的自然过程中经历了向Nanog表达的进化，并且Nanog创建了一个保护肿瘤免受CTL攻击的微环境。我们的具体目标是：(1)表征在抗肿瘤免疫反应中活动物中向Nanog实时表达的肿瘤进化；(2)表征Nanog在建立免疫抑制肿瘤微环境中的作用；以及(3)表征Nanog协调免疫逃逸的分子机制。该项目的成功实施将引入一种在分子水平上实时探索肿瘤进化的平台技术，并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关键的洞察。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。本研究的结果将对癌症的临床诊断和治疗具有重要意义。

DESCRIPTION (provided by applicant): Emergence of a stem-like state in the tumor and adaptation to host immune defenses are in large part responsible for disease progression and recurrence in cancer patients. Thus, to reduce the mortality rate due to cancer, it is important understand the manner through which the tumor acquires a stem-like state and through which it evades immune surveillance. We recently found that during immune selection, cancer cells gain expression of Nanog, a master transcription factor pivotal in the maintenance and self-renewal of pluripotent stem cells. Nanog confers a stem-like and immune-resistant phenotype to these cancer cells, and inhibition of Nanog leads to tumor eradication by CD8+ cytotoxic T lymphocytes (CTLs) in mice. Furthermore, we found that Nanog is abundant in a wide variety of human cancer types, and Nanog expression in tumor tissue correlates with stage of disease and overall survival of patients with cervical neoplasia. Our studies thus far have identified Nanog as a prime molecular target for cancer therapy and suggest a link between the stem- like state in cancer and immune surveillance. The purpose of the current project is to investigate the role of Nanog in tumor immune escape. We hypothesize that cancer cells undergo evolution towards Nanog expression in the natural course of host immune surveillance, and that Nanog creates a microenvironment that protects the tumor from attack by CTLs. Our specific aims are to: (1) Characterize tumor evolution towards Nanog expression in real-time in live animals during an anti-tumor immune response; (2) Characterize the role of Nanog in setting up an immune-suppressive tumor microenvironment; and (3) Characterize the molecular mechanisms through which Nanog coordinates immune escape. The successful implementation of this project will introduce a platform technology to explore tumor evolution at the molecular level in real-time and provide key insight into the mechanisms that mediate tumor adaptation in the natural setting of the host immune system. Also, 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 implications for the clinical diagnosis and management of cancer.