The Effect of Tumor Burden on Peripheral cDC1 Activation and Functionality

项目总结/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、血液和骨髓。安装从头免疫 肿瘤清除需要外周和肿瘤内的反应。常规I型树突状细胞 CDC 1是这种反应的关键组成部分，也是许多免疫疗法成功的关键组成部分。肿瘤是 已知其损害TME中cDC的功能，但关于外周cDC的问题仍然存在： 肿瘤的免疫抑制机制延伸到脾脏中的cDC？在哪些方面， 免疫抑制途径影响CD 8 T细胞启动能力的cDC 1 s？回答这些问题将 促进我们对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。 发展这项提议将检验这样一个假设，即在肿瘤周围的可溶性因子， 宿主改变cDC 1引发从头CD 8 T细胞应答继发感染的能力。目标1 该提案将确定受损的脾cDC 1激活与肿瘤负荷的上游介质。目的2 将确定在肿瘤负荷的背景下由脾cDC 1引发的缺陷性CD 8 T细胞的机制。 该研究方法将使用包括单细胞蛋白质组学分析在内的多种方法进行 (flow流式细胞术和飞行时间质谱流式细胞术（CyTOF））、成像研究、离体共培养和体内共培养。 体内测定。这些拟议的研究将是第一批评估以下方法的机制研究， 肿瘤负荷可改变外周cDC功能。这可能会导致新的发现的途径 重要的是在适应性免疫反应，以血液传播的感染，并导致进一步了解 树突状细胞和T细胞相互作用的研究。翻译，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。此外，这项工作将更好地 为癌症治疗本身提供信息的免疫治疗方法，特别是在过继细胞治疗领域- 具体地，如何进一步从外周细胞或过继性T细胞疗法中获得树突细胞疫苗， 提高这项研究项目和奖学金培训将在一个顶级资助的研究 机构，加州大学弗朗西斯科分校（UCSF），在马修斯皮策博士的实验室 还有刘易斯·拉尼尔医生拉尼尔博士在免疫细胞生物学方面取得了广泛的基础性发现， 他的职业生涯。Spitzer博士是一名研究人员，具有系统癌症免疫学方法的专业知识， 树突状细胞生物学这些导师和机构将提供丰富的培训环境， 建议研究和发展必要的专业技能，继续学术研究生涯。

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.