Immunity to commensal papillomaviruses for cancer therapy

项目概要/摘要： 微生物组领域的研究主要集中在肠道细菌在肠道中的有益作用上。 调节组织内环境稳定和免疫反应。然而，病毒组在支持 人类健康尚未得到探索。我们建议调查肠道病毒组及其有益的影响 对屏障上皮的组织稳态和癌症保护的作用。根据我们最近发现的 低风险乳腺乳头状瘤病毒的有益作用和对它们的免疫保护皮肤 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癌症， 患者自身的病毒组和免疫系统精确地靶向屏障内的早期恶性克隆 上皮细胞特别是，屏障中广泛存在的人乳头瘤病毒（HPV）， 上皮细胞和成年人的免疫系统控制这些病毒的能力将提供一个独特的 有机会确定肠道病毒，上皮肿瘤和免疫系统的相互作用。到 为了实现这一点，我们将使用乳头瘤病毒定植的新小鼠模型来（1）确定 人乳头状瘤病毒对维持暴露于环境致癌物的上皮细胞内环境稳定的作用（2） 确定激活靶向恶性细胞的抗病毒T细胞所需的先天免疫因子 而保留病毒阳性的正常组织，和（3）确定在口腔中定植的乳头状瘤病毒的作用。 粘膜对致癌物诱发的头颈部癌。拟议研究的结果将建立 在对抗癌症发展的早期阶段， 是指利用患者自身的病毒组和免疫细胞预防和治疗非病毒性上皮癌。

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.