Rewiring the myeloid cell response to adjuvants to improve tumor control

这一建议的关键初步数据是，与公认的教条相反，在暴露于 内源性免疫佐剂MyD 88向巨噬细胞传递负信号， 放射治疗我们证明，在免疫原性差的肿瘤中，巨噬细胞在 暴露于垂死的癌细胞，使得它们抑制肿瘤免疫环境的多种特征。 这包括T细胞控制残留疾病的能力和树突状细胞成熟。的目的 建议是了解这种抑制发生的机制，确定对 巨噬细胞抑制，并利用这一点来确定患者群体，将对目前的 治疗我们假设，暴露于垂死的细胞重新连接巨噬细胞信号，使先天性 MyD 88的激活抑制局部肿瘤免疫。本研究的具体目的是：1.测试 MyD 88的缺失阻止NF κ B驱动的抗炎基因转录并导致 增加IRF 3驱动的IFN转录; 2：检验通过Mertk介导的“重新布线”的信号传导的假设 改变了对佐剂的反应，限制了肿瘤环境中的免疫功能;以及3： 测试MyD 88基因表达模式与患者预后不良相关的假设。我们的研究 设计结合了多个真实胰腺肿瘤模型的CT引导放射治疗，并使用 RT剂量和分次的范围。这些与独特的敲除和测定相结合，使我们能够 在体外和体内鉴定不同骨髓反应。我们对临床样本的分析使用高质量的 生物信息学方法使我们能够评估肿瘤环境对生物反应的影响 与患者样本中的先天性佐剂有关。

The critical preliminary data for this proposal is that contrary to the accepted dogma, following exposure to endogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control by radiation therapy. We demonstrate that in poorly immunogenic tumors, macrophages are rewired following exposure to dying cancer cells such that they suppress multiple features of the tumor immune environment. This includes the ability of T cells to control residual disease, and dendritic cell maturation. The aim of this proposal is to understand the mechanisms by which this suppression occurs, identify the regulation of macrophage suppression, and use this to identify patient populations that will respond poorly to current therapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innate activation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test the hypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results in increased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated ‘rewiring’ of macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3: Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our study design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to identify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patient samples.