The Effect of Tumor Burden on Peripheral cDC1 Activation and Functionality

项目摘要/摘要 肿瘤破坏免疫系统的动态平衡，改变免疫细胞的组成和表型 肿瘤微环境(TME)、淋巴结、脾、血和骨髓。建立一种从头免疫 肿瘤清除需要外周和肿瘤内的反应。常规型I型树突状细胞 (CDC1s)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到脾中的CDC？这些是以什么方式实现的？ 免疫抑制途径影响CD8T细胞对CDC1s？回答这些问题将会 增进我们对CDC生物学、肿瘤发病机制的了解，更好地指导有效的免疫治疗 发展。这一提议将检验这样一种假设，即肿瘤外围的可溶性因子承担着 宿主改变了CDC1s启动CD8T细胞对二次感染的反应的能力。目标1 该提案将确定与肿瘤负担相关的脾cDC1激活受损的上游介质。目标2 将在肿瘤负担的背景下确定脾CD8缺陷T细胞由CDC1s启动的机制。 这一研究方法将使用包括单细胞蛋白质组分析在内的各种方法进行 (流式细胞术和飞行时间质量细胞术(CyTOF))，成像研究，体外共培养，以及 活体化验。这些拟议的研究将是评估方法的一些首批机械性研究 肿瘤负荷可以改变外周血CDC功能。这可能会导致通路的新发现 在血液传播感染的获得性免疫反应中很重要，并有助于加深我们对 树突状细胞和T细胞的相互作用。翻译过来，这项工作将提高我们对癌症的理解 这将有助于了解患者对感染的易感性，并揭示潜在的治疗措施。此外，这项工作将更好地 告知癌症治疗本身的免疫治疗方法，特别是在过继细胞治疗领域- 具体地说，从外周细胞衍生的树突状细胞疫苗或过继T细胞疗法如何进一步 改进了。这项研究项目和奖学金培训将在一个顶级资助的研究项目中进行 加州大学旧金山分校(UCSF)，马修·斯皮策博士的实验室 还有刘易斯·拉尼尔博士。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 在他的职业生涯中。斯皮策博士是一名研究人员，在系统癌症免疫学方法和 树突状细胞生物学。这些导师和机构将提供丰富的培训环境，以完成 为继续学术研究事业所需的拟议研究和发展专业技能。

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.