Immunity to commensal papillomaviruses for cancer therapy

项目摘要/摘要： 微生物组领域的研究在很大程度上集中在共生细菌的有益作用上 调节组织动态平衡和免疫反应。然而，病毒在支持 人类的健康还没有被探讨过。我们建议调查共生病毒体及其有益影响 屏障上皮细胞的组织动态平衡与癌症保护。从我们最近发现的 低危共生乳头瘤病毒及其免疫在保护皮肤中的有益作用 针对致癌物驱动的癌症，我们提出了一种全新的方法来预防非病毒性癌症，方法是使用 患者自身的病毒和免疫系统精确定位屏障内的早期恶性克隆 上皮细胞。尤其是在屏障中广泛存在的共生性人乳头瘤病毒(HPV) 上皮细胞和有能力控制这些病毒的成人免疫系统将提供一种独特的 有机会确定共生病毒、上皮性肿瘤和免疫系统之间的相互作用。至 为此，我们将使用新的小鼠乳头瘤病毒定植模型来(1)确定 共生HPV对环境致癌物暴露的上皮细胞动态平衡的维持作用(2) 识别针对恶性细胞的抗病毒T细胞激活所需的先天免疫因子 同时保留病毒阳性的正常组织，以及(3)确定定植于口腔的乳头瘤病毒的作用 粘膜上的致癌物可诱发头颈癌。拟议研究的结果将确定 共生病毒体在抗击癌症早期发展阶段的基础作用，并提供 使用患者自身的病毒和免疫细胞预防和治疗非病毒性上皮性癌症的手段。

Project Summary/Abstract: Research in the field of microbiome has largely focused on the beneficial effects of commensal bacteria in regulating tissue homeostasis and the immune responses. However, a commensal role for virome in supporting human health has not been explored. We propose to investigate the commensal virome and its beneficial impact on tissue homeostasis and cancer protection in barrier epithelia. Informed by our recent discovery of the beneficial role of low-risk commensal papillomaviruses and the immunity against them in protecting the skin against carcinogen-driven cancer, we propose a completely novel approach to prevent nonviral cancers by using the patients’ own virome and the immune system to precisely target early malignant clones within the barrier epithelia. In particular, the widespread presence of commensal human papillomaviruses (HPVs) in barrier epithelia and the ability of a competent immune system in adults to control these viruses will provide a unique opportunity to determine the interplay of commensal viruses, epithelial tumors and the immune system. To accomplish this, we will use novel mouse models of papillomavirus colonization to (1) determine the impact of commensal HPVs on maintaining the homeostasis of epithelium exposed to environmental carcinogens, (2) identify the innate immune factors that are required for the activation of antiviral T cells targeting malignant cells while spare the virus-positive normal tissue, and (3) determine the role of papillomaviruses that colonize the oral mucosa on the carcinogen-induced head and neck cancer. The outcomes of the proposed research will establish a fundamental role for commensal virome in combating the early stages of cancer development and provide the means to prevent and treat nonviral epithelial cancers using patients’ own virome and the immune cells.