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

基本信息

批准号：
10642927
负责人：
Rachel DeBarge
金额：
$ 3.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642927
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 Cell physiology Cells Cellular biology Coculture Techniques Cytometry Data Defect Dendritic Cell Vaccine Dendritic Cells Dendritic cell activation Development Environment Excision Fellowship Flow Cytometry 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 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 cancer therapy career chemokine cytokine cytotoxic CD8 T cells experimental study imaging study improved in vivo interest lymph nodes migration novel pathogen research and development response secondary infection skills success tumor tumor immunology tumor microenvironment uptake

项目摘要

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。肿瘤清除需要外周和瘤内的常规反应。 (cDC1) 是这种反应的关键组成部分，也是许多肿瘤免疫疗法成功的关键。已知会损害 TME 中 CDC 的功能，但关于外围 CDC 的问题仍然存在：如何肿瘤的免疫抑制机制通过什么方式延伸到脾脏中的 cDC？免疫抑制途径会影响 cDC1 的 CD8 T 细胞启动能力吗？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该提案将检验肿瘤外周可溶性因子的假设。改变宿主 cDC1 引发 CD8 T 细胞对继发感染的反应的能力。该提案将确定脾 cDC1 激活受损与肿瘤负荷的上游介质。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这些拟议的研究将是评估这些方法的首批机制研究之一。肿瘤负荷可以改变外周 CDC 功能，这可能导致通路的新发现。对于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从转化角度来说，这项工作将提高我们对癌症的理解。此外，这项工作将更好地了解患者对感染的易感性并揭示潜在的治疗干预措施。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该研究项目和奖学金培训将在顶级资助的研究中进行。加州大学旧金山分校 (UCSF) Matthew Spitzer 博士的实验室刘易斯·拉尼尔 (Lewis 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。 Spitzer 博士是一位在系统癌症免疫学方法和领域具有专业知识的研究者。这些导师和机构将为完成树突状细胞生物学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。