Anti-Tumor Mechanisms of Intratumoral Stimulatory Dendritic Cells

瘤内刺激树突状细胞的抗肿瘤机制

基本信息

批准号：
9311801
负责人：
MATTHEW F KRUMMEL
金额：
$ 35.04万
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：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311801
关键词：
Affect Ally Antigen-Presenting Cells Antigens Area Biology CD8-Positive T-Lymphocytes CSF1 gene CTLA4 gene Cancer Model Cancer Patient Cell Communication Cell Count Cell Density Cell physiology Cells Cellular biology Combined Modality Therapy Competence Data Dendritic Cells Diagnostic Discipline Disease FLT3LG gene Flow Cytometry Frequencies Goals Grant Hand Human Image Immune Immune response Immune system Immunity Individual Lead Ligands Malignant Neoplasms Methods Molecular Mus Myelogenous Myeloid Cells Pathway interactions Pharmaceutical Preparations Play Population Process Production Reagent Regulation Reporter Research Personnel Role Series Specific qualifier value Stimulus System Systems Biology T cell response T cell therapy T-Lymphocyte T-Lymphocyte Subsets Therapeutic Tissues Tumor Antigens Vertebral column Work base cancer survival checkpoint therapy cytokine empowered experimental study human disease imaging system immune checkpoint blockade improved in vivo innovation interest lymph nodes mouse model next generation novel therapeutics response therapeutic development trafficking tumor tumor microenvironment tumor progression

项目摘要

Project Summary/Abstract Treating the immune response within tumors is a major focus of new therapeutic development. Much of the focus has been place on T cells, in particular via checkpoint therapies such as anti-CTLA4 or anti-PD1. Little is currently known of how individual populations of myeloid cells can be partners for T cells. We have recently isolated rare populations of myeloid cells that appear critical for robust responses but we don't yet fully understand how they work. We hypothesize that rare stimulatory dendritic cells traffic antigens and stimulate T cell according to specialized rules and that harnessing and modulation of this pathway is part of the reason that checkpoint blockades may work. We further hypothesize that specific tissue-based cells are responsible for upregulating the critical cytokine to make stimulatory dendritic cells but that tissue production is dysregulated in cancer and possibly improved with checkpoint therapies. In this proposal we will be vastly extending an approach that my lab has been pursuing over the last few years. Specifically we will be extending our cell-biology based studies of these critical cells (Aim1) to understand how they play a fundamental role in antigen trafficking. Additionally, we will seek to understand how they hand off antigen to other antigen-presenting cells in the lymph node to engage T cells (Aim2) and how both of these processes are affected by checkpoint blockades. Finally, in aim 3, we will seek to understand the normal and intratumoral production of the cytokine Flt3L, a key player in regulating the number of these rare cells. At the end of this work, we will understand how these intratumoral myeloid cells function on their own and in concert with T cell therapies.

项目概要/摘要治疗肿瘤内的免疫反应是新疗法开发的一个主要焦点。大部分的人们的注意力集中在 T 细胞上，特别是通过抗 CTLA4 或抗 PD1 等检查点疗法。小的是目前已知单个骨髓细胞群如何成为 T 细胞的伴侣。我们最近有分离出罕见的骨髓细胞群，它们似乎对强有力的反应至关重要，但我们尚未完全了解了解它们是如何工作的。我们假设罕见的刺激性树突状细胞运输抗原并刺激 T 细胞遵循专门的规则，并且利用和调节该途径是部分原因检查站封锁可能会起作用。我们进一步假设特定的组织细胞负责上调关键细胞因子以产生刺激性树突状细胞，但组织生产是癌症中失调，并可能通过检查点疗法得到改善。在这个提案中，我们将极大地扩展我的实验室过去几年一直在追求的方法。具体来说，我们将扩展对这些关键细胞的基于细胞生物学的研究（目标1），以了解如何它们在抗原贩运中发挥着重要作用。此外，我们将设法了解他们如何移交淋巴结中其他抗原呈递细胞的抗原以吸引 T 细胞 (Aim2) 以及这两者如何进程受到检查点封锁的影响。最后，在目标 3 中，我们将寻求了解正常和肿瘤内产生细胞因子 Flt3L，它是调节这些稀有细胞数量的关键因素。在这项工作结束时，我们将了解这些瘤内骨髓细胞如何自行发挥作用并与 T 细胞疗法相配合。