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Immunity to commensal papillomaviruses for cancer therapy

对共生乳头瘤病毒的免疫用于癌症治疗

基本信息

批准号：
10397664
负责人：
Shadmehr Demehri
金额：
$ 52.74万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397664
关键词：
Address Adult Aerodigestive Tract Aging Antigen Presentation Antigens Architecture CD8-Positive T-Lymphocytes Cancerous Carcinogens Carcinoma Cells Clinical Research Clonal Expansion Complement Development Elderly Environmental Carcinogens Epithelial Epithelial Cells Exposure to Foundations Goals Head and Neck Cancer Health Homeostasis Human Human Papillomavirus Hyperplasia Hypersensitivity skin testing Immune Immune response Immune signaling Immune system Immunity Immunocompetent Immunologic Factors Individual Lesion Low risk HPV Maintenance Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Mucous Membrane Mus Mutate Mutation Nature Normal tissue morphology Oral mucous membrane structure Outcome Outcomes Research Papillomavirus Patients Pattern Persons Play Process Proliferating Research Risk Role Skin Skin Cancer Skin Carcinogenesis Skin colonization T cell response T-Cell Activation T-Cell Depletion T-Lymphocyte Testing Tissues Treatment Cost UV carcinogenesis UV induced Ultraviolet Rays United States Vaccination Viral Antigens Virus Work antiviral immunity cancer cell cancer prevention cancer therapy carcinogenesis carcinogenicity cell injury chemokine commensal bacteria cytokine head and neck cancer patient high risk human virome improved innate immune pathways innovation microbiome mouse model mucosal site normal microbiota novel novel strategies premalignant prevent protective effect reproductive tract transcriptome sequencing tumor ultraviolet virome

项目摘要

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.

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。