CD91 and cancer immunosurveillance

CD91 和癌症免疫监视

基本信息

批准号：
10524051
负责人：
Robert J Binder
金额：
$ 34.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-16 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524051
关键词：
Adoptive Transfer Antigen-Presenting Cells Antigens Automobile Driving Binding Proteins Cells Chemicals Clinical Cross Presentation Cross-Priming Data Dendritic Cells Development Event Evolution Foundations Generations Genetic Polymorphism HIV Heat shock proteins Hematopoietic Human Immune Immune response Immune system Immunity Immunologic Surveillance Immunologics Immunology In Situ Individual Knockout Mice Knowledge Laboratories Lead Ligands Malignant Neoplasms Mediating Modeling Molecular Molecular Chaperones Mus Mutation NK Cell Activation Natural Killer Cells Outcome Pathway interactions Patients Peptides Population Positioning Attribute Predisposition Productivity Publishing Qualifying Research Resistance Role Shapes Signal Transduction Stimulus T cell response T-Lymphocyte Tumor Antigens Tumor Escape Tumor-Derived Vaccination Virus Diseases Wild Type Mouse Work anti-tumor immune response conditional knockout cytokine insight melanoma neoantigens novel prevent prognostic receptor response tool tumor tumor immunology

项目摘要

The immune system recognizes aberrant cells and eliminates them prior to emergence of nascent tumors. This prevents progression of many malignancies. In the absence of such immunity in mice or humans, multiple and frequent tumors are generated. Current immunosurveillance model involves the priming of T cell and NK cell immunity. The gap in knowledge in this model is raised in two questions; (1) What is the molecular mechanism for cross-priming T cell responses in the context of the negligible amount of antigen available at the early stages of nascent tumor development? (2) What is the stimuli for co-stimulation of T cell priming and activation of NK cells. Our work has demonstrated that tumor-derived heat shock proteins (HSPs), introduced during vaccination, are super-efficient at cross-presentation of limited amounts of their chaperoned tumor (peptide) antigen. HSPs are also capable of initiating signals for co-stimulation. Both events require the HSP receptor, CD91, expressed on dendritic cells and together allow for priming potent tumor-specific T cells. The release of cytokines by DCs stimulated with HSPs enhances the T cell responses and activates NK cells. Our hypothesis is that when tumor antigen levels are limiting, as in nascent emerging tumors, the HSP-CD91 pathway is essential for cross-priming of anti-tumor immune responses. In humans, immune responses to cancer are influenced by variable expression levels of CD91 and its polymorphism, driving the clinical and translational relevance of this proposal. In this application we will determine how CD91 serves as an essential conduit for initiating responses for cancer immunosurveillance.

免疫系统识别异常细胞并在出现新生肿瘤之前消除它们。这防止许多恶性肿瘤的进展。在没有小鼠或人类中这种免疫力的情况下，多个和经常产生肿瘤。当前的免疫监视模型涉及T细胞和NK细胞的启动免疫。这个模型中的知识差距是在两个问题中提出的。（1）什么是分子机制在早期可用的抗原量可忽略不计的情况下，用于交叉染色的T细胞反应肿瘤发育的阶段？（2）共同刺激T细胞启动和激活的刺激是什么 NK细胞。我们的工作表明，在疫苗接种，在其伴侣肿瘤（肽）的交叉表现方面具有超高效率抗原。 HSP还能够启动信号进行共刺激。这两个事件都需要HSP受体， CD91，在树突状细胞上表达，共同允许启动有效的肿瘤特异性T细胞。发行通过HSP刺激的DC细胞因子可增强T细胞反应并激活NK细胞。我们的假设是当肿瘤抗原水平受到限制时，如新生的新兴肿瘤时，HSP-CD91途径为抗肿瘤免疫反应的交叉染色至关重要。在人类中，对癌症的免疫反应是受CD91的可变表达水平及其多态性的影响，推动临床和翻译该提议的相关性。在此应用中，我们将确定CD91如何用作必需的管道引发对癌症免疫监视的反应。