The Effect of Tumor Burden on Peripheral cDC1 Activation and Functionality

肿瘤负荷对外周 cDC1 激活和功能的影响

• 批准号: 10442408
• 负责人: Rachel DeBarge
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442408
• 关键词: Adoptive Cell Transfers; Affect; Agonist; Antigen Presentation; Antigen-Presenting Cells; Antigens; Architecture; Biological Assay; Biology; Blood; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD80 gene; CSF3 gene; California; Cancer Patient; Cell Communication; Cells; Cellular biology; Coculture Techniques; Cytometry; Data; Defect; Dendritic Cell Vaccine; Dendritic Cells; Development; Environment; Excision; Fellowship; Flow Cytometry; Foundations; Functional disorder; Funding; Goals; Homeostasis; I-antigen; Image; Immune; Immune response; Immune system; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infection; Institution; Interruption; Laboratories; Ligation; Listeria monocytogenes; Mediating; Mediator of activation protein; Mentors; Methods; Mixed Lymphocyte Culture Test; Mus; Myeloid Cell Suppression; Myeloid-derived suppressor cells; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Population; Predisposition; Process; Proteomics; Research; Research Personnel; Research Project Grants; San Francisco; Secondary to; Spleen; Surface; System; T cell response; T cell therapy; T-Cell Proliferation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic Intervention; Time; Training; Tumor Burden; Universities; Work; adaptive immune response; anti-CTLA4; anti-cancer; bone; cancer therapy; career; chemokine; cytokine; cytotoxic CD8 T cells; experimental study; imaging study; improved; in vivo; lymph nodes; migration; novel; pathogen; research and development; response; secondary infection; skills; success; tumor; tumor immunology; tumor microenvironment; uptake

PROJECT SUMMARY/ABSTRACT Tumors disrupt the homeostasis of the immune system, altering immune cell composition and phenotype in the tumor microenvironment (TME), lymph nodes, spleen, blood, and bone marrow. Mounting a de novo immune response both peripherally and intratumorally is required for tumor clearance. Conventional type I dendritic cells (cDC1s) are a critical component of this response and in the success of many immunotherapies. Tumors are known to impair the function of cDCs in the TME, but questions about peripheral cDCs remain: how do immunosuppressive mechanisms of tumors extend to cDCs in the spleen? In what ways do these immunosuppressive pathways affect the CD8 T cell priming abilities of cDC1s? Answering these questions will advance our understanding of cDC biology, tumor pathogenesis, and better inform effective immunotherapy development. This proposal will test the hypothesis that soluble factors in the periphery of tumor-burdened hosts alter the ability of cDC1s to prime de novo CD8 T cell responses to secondary infection. Aim 1 of this proposal will determine the upstream mediators of impaired splenic cDC1 activation with tumor burden. Aim 2 will determine the mechanism of defective CD8 T cell priming by splenic cDC1s in the context of tumor burden. This research approach will be carried out using a variety of methods including single-cell proteomic analysis (flow cytometry and Mass Cytometry by Time of Flight (CyTOF)), imaging studies, ex vivo co-cultures, and in vivo assays. These proposed studies will be some of the first mechanistic studies to assess ways that tumor burden can alter peripheral cDC functionality. This could result in the novel discovery of pathways important in the adaptive immune response to blood borne infections and result in furthering our understanding of dendritic cell and T cell interactions. Translationally, this work will improve our understanding of cancer patients’ susceptibility to infections and reveal potential therapeutic interventions. Further, this work will better inform immunotherapy approaches for cancer treatment itself, especially in the adoptive cell therapy field – specifically, how dendritic cell vaccines derived from peripheral cells or adoptive T cell therapy can be further improved. This research project and fellowship training will be conducted at a top-funded research institution, the University of California, San Francisco (UCSF), in the laboratories of Dr. Matthew Spitzer and Dr. Lewis Lanier. Dr. Lanier has made extensive foundational discoveries in immune cell biology over the course of his career. Dr. Spitzer is an investigator with expertise in systems cancer immunology approaches and dendritic cell biology. These mentors and institution will provide a rich training environment for completion of the proposed research and development of professional skills necessary for a continued academic research career.

项目概要/摘要 肿瘤破坏免疫系统的稳态，改变免疫细胞的组成和表型 肿瘤微环境（TME）、淋巴结、脾脏、血液和骨髓。安装从头免疫 肿瘤清除需要外周和瘤内的反应。常规I型树突状细胞 (cDC1) 是这种反应以及许多免疫疗法成功的关键组成部分。肿瘤是 已知会损害 TME 中 CDC 的功能，但关于外周 CDC 的问题仍然存在：如何 肿瘤的免疫抑制机制延伸至脾脏中的cDC？这些通过什么方式 免疫抑制途径影响 cDC1 的 CD8 T 细胞启动能力？回答这些问题将 增进我们对 CDC 生物学、肿瘤发病机制的理解，并更好地为有效的免疫治疗提供信息 发展。该提案将检验以下假设：肿瘤负载周围的可溶性因子 宿主改变 cDC1 启动 CD8 T 细胞对继发感染作出反应的能力。这个目标1 该提案将确定脾脏 cDC1 激活受损与肿瘤负荷的上游介质。目标2 将确定在肿瘤负荷背景下脾 cDC1 启动缺陷 CD8 T 细胞的机制。 该研究方法将使用多种方法进行，包括单细胞蛋白质组分析 （流式细胞术和飞行时间质谱细胞术 (CyTOF)）、成像研究、离体共培养以及体内 体内测定。这些拟议的研究将是首批机制研究之一，旨在评估以下方法： 肿瘤负荷可以改变外周 CDC 功能。这可能会导致途径的新发现 对血源性感染的适应性免疫反应很重要，并有助于加深我们的理解 树突状细胞和 T 细胞相互作用。从转化角度来说，这项工作将提高我们对癌症的理解 患者对感染的易感性并揭示潜在的治疗干预措施。进一步，这项工作将更好 为癌症治疗本身的免疫治疗方法提供信息，特别是在过继细胞治疗领域 – 具体来说，源自外周细胞的树突状细胞疫苗或过继性 T 细胞疗法如何进一步 改善了。该研究项目和奖学金培训将在顶级资助的研究机构进行 加州大学旧金山分校 (UCSF) 的 Matthew Spitzer 博士实验室 和刘易斯·拉尼尔博士。 Lanier 博士多年来在免疫细胞生物学领域取得了广泛的基础性发现 他的职业生涯。 Spitzer 博士是一位研究人员，在系统癌症免疫学方法和 树突状细胞生物学。这些导师和机构将为完成课程提供丰富的培训环境 提议研究和发展持续学术研究生涯所需的专业技能。