CD91 and cancer immunosurveillance

CD91 和癌症免疫监视

• 批准号: 10308038
• 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
• 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/10308038
• 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

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消除。这 防止许多恶性肿瘤的进展。在小鼠或人类中缺乏这种免疫力的情况下， 经常产生肿瘤。目前的免疫监视模型涉及T细胞和NK细胞的启动 免疫力这个模型的知识上的差距是由两个问题引起的：（1）分子机制是什么 对于在早期可获得的抗原量可忽略不计的情况下的交叉引发T细胞应答， 新生肿瘤的发展阶段？(2)T细胞启动和激活的共刺激的刺激因素是什么 NK细胞。我们的工作已经证明，肿瘤源性热休克蛋白（HSPs），在肿瘤生长过程中引入， 疫苗接种，在交叉呈递有限数量的它们的伴侣肿瘤（肽）方面是超级有效的。 抗原的热休克蛋白也能够启动信号共刺激。这两个事件都需要HSP受体， 在树突状细胞上表达的CD91一起允许引发有效的肿瘤特异性T细胞。释放 HSPs刺激的DC产生的细胞因子增强T细胞应答并激活NK细胞。我们的假设 当肿瘤抗原水平有限时，如在新生肿瘤中，HSP-CD91途径是 对于交叉引发抗肿瘤免疫反应至关重要。在人类中，对癌症的免疫反应是 受CD91及其多态性的可变表达水平的影响， 这一建议的相关性。在本申请中，我们将确定CD91如何作为一个重要的管道， 启动癌症免疫监视的反应。