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CD91 and cancer immunosurveillance

CD91 和癌症免疫监视

基本信息

批准号：
9897031
负责人：
Robert J Binder
金额：
$ 35.49万
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/9897031
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 Peptides Population Positioning Attribute Predisposition Publishing Research Resistance Role Shapes Signal Transduction Stimulus T cell response T-Lymphocyte Tumor Antigens Tumor Escape Tumor-Derived Vaccination Virus Diseases 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，并在新生肿瘤出现之前将其清除。这