Anti-Tumor Mechanisms of Intratumoral Stimulatory Dendritic Cells

项目摘要/摘要 治疗肿瘤内的免疫反应是新的治疗方法发展的主要焦点。世界上大部分的 关注的焦点是T细胞，特别是通过检查点治疗，如抗CTLA4或抗PD1。小才是 目前已知单个髓系细胞群体如何成为T细胞的伴侣。我们最近做了 孤立的稀有髓系细胞群体似乎对强大的反应至关重要，但我们还没有完全 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和刺激 根据特殊规则对细胞进行测试，利用和调节这一途径是部分原因 检查站封锁可能会奏效。我们进一步假设特定的基于组织的细胞负责 为了上调关键细胞因子以产生刺激性树突状细胞，但组织产生的 癌症中的调节失调，并可能通过检查点疗法得到改善。 在这项提案中，我们将极大地扩展我的实验室在过去几年中一直在追求的方法。 具体地说，我们将扩展我们对这些关键细胞的细胞生物学研究(Aim1)，以了解如何 它们在抗原运输中发挥着重要作用。此外，我们将努力了解他们是如何将 抗原到淋巴结中的其他抗原提呈细胞与T细胞结合(AIM2)以及这两者如何 进程受到检查站封锁的影响。最后，在目标3中，我们将寻求理解常态和 瘤内产生细胞因子Flt3L，这是调节这些稀有细胞数量的关键因素。 在这项工作的最后，我们将了解这些肿瘤内的髓系细胞是如何自身发挥作用的。 并配合T细胞疗法。

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.