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：
10625967
负责人：
Shadmehr Demehri
金额：
$ 52.11万
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/10625967
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 Cells Epithelium Exposure to Foundations Goals Head and Neck Cancer Health Homeostasis Human Human Papillomavirus Hyperplasia 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 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主要集中在共生细菌在调节组织稳态和免疫反应。但是，病毒瘤在支持中的共同作用人类健康尚未探索。我们建议调查共生病毒蛋白及其有益的影响关于屏障上皮的组织体内稳态和癌症保护。我们最近发现的低风险的共生乳头瘤病毒的有益作用及其在保护皮肤方面的免疫力针对致癌癌的癌症，我们提出了一种完全新颖的方法，以防止非病毒癌患者自己的病毒蛋白和免疫系统，以精确靶向障碍物内的早期恶性克隆上皮。特别是，屏障中共生人乳头瘤病毒（HPV）的宽度存在上皮和成年人控制这些病毒的能力的能力将提供独特的确定共生病毒，上皮肿瘤和免疫系统的相互作用的机会。到这样做，我们将使用新颖的乳头瘤病毒定植的鼠标模型来确定在维持暴露于环境致癌物的上皮的稳态方面的共生HPV，（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虽然避免病毒阳性正常组织，并且（3）确定乳头瘤病毒的作用致癌物引起的头颈癌上的粘膜。拟议研究的结果将建立共生病毒瘤在打击癌症发展的早期阶段的基本作用，并提供使用患者自己的病毒蛋白和免疫细胞预防和治疗非病毒上皮癌的手段。