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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：
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的有益作用上调节组织稳态和免疫反应。然而，病毒组在支持人类健康尚未被探索。我们建议研究共生病毒组及其有益影响关于屏障上皮的组织稳态和癌症保护。根据我们最近的发现低风险共生乳头瘤病毒及其免疫力在保护皮肤方面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患者自身的病毒组和免疫系统可以精确地瞄准屏障内的早期恶性克隆上皮细胞。特别是，屏障中广泛存在共生人乳头瘤病毒（HPV）上皮细胞和成人强大的免疫系统控制这些病毒的能力将提供独特的确定共生病毒、上皮肿瘤和免疫系统之间相互作用的机会。到为了实现这一目标，我们将使用乳头瘤病毒定植的新型小鼠模型来（1）确定共生 HPV 维持暴露于环境致癌物的上皮细胞的稳态，(2) 识别激活针对恶性细胞的抗病毒 T 细胞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质诱发头颈癌。拟议研究的结果将确定共生病毒组在对抗癌症发展的早期阶段中发挥着重要作用，并提供是指利用患者自身的病毒组和免疫细胞来预防和治疗非病毒性上皮癌。