Rewiring the myeloid cell response to adjuvants to improve tumor control

重新连接骨髓细胞对佐剂的反应以改善肿瘤控制

基本信息

批准号：
10064141
负责人：
Michael James Gough
金额：
$ 37.74万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-02 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064141
关键词：
Adjuvant Anti-Inflammatory Agents Apoptotic Bioinformatics Biological Biological Assay Cell Maturation Cells Cessation of life Chemotherapy and/or radiation Clinical Collection Cross Presentation Cytotoxic Chemotherapy Data Data Set Dendritic Cells Dose Fractionation Environment Exposure to Failure Gene Expression Profile Genes Genetic Transcription HMGB1 gene Heat shock proteins IRF3 gene Immune Immunity Immunologic Adjuvants Immunotherapy In Vitro Interferons Intervention Knock-out Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Myelogenous Myeloid Cells NF-kappa B Necrosis Outcome Pancreas Pathologic Pathology Patient-Focused Outcomes Patients Pre-Clinical Model Process RNA Radiation therapy Regulation Research Design Residual Tumors Sampling Signal Transduction Stimulator of Interferon Genes T cell response T-Lymphocyte Testing Therapeutic Toll-like receptors Transcriptional Regulation Treatment Failure Tumor Biology Tumor Immunity Tumor-associated macrophages cancer cell cancer type checkpoint therapy chemotherapy environmental enrichment for laboratory animals extranuclear DNA immune function immunogenic improved improved outcome in vivo macrophage novel pancreatic cancer model patient population patient response patient subsets prevent response sensor success tumor

项目摘要

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.

该提案的关键初步数据是与公认的教条形成对比内源性免疫调节器MyD88向巨噬细胞传达负信号，巨噬细胞限制了肿瘤控制放射治疗。我们证明，在免疫原性肿瘤不良，巨噬细胞在暴露于垂死的癌细胞，使它们抑制肿瘤免疫环境的多个特征。这包括T细胞控制残留疾病的能力和树突状细胞成熟。这个目的提案是要了解这种抑制的机制，确定调节的调节巨噬细胞抑制，并用它来识别患者人群对当前的反应不佳疗法。我们假设暴露于垂死的细胞重新布线巨噬细胞信号，使得先天 MyD88的激活抑制局部肿瘤免疫。这项研究的具体目的是1：测试假设MyD88的丢失阻止NFKB驱动 - 抗抗炎基因转录，并导致 IRF3驱动的IFN转录增加； 2：测试通过MERTK介导的“重新布线”信号传导的假设巨噬细胞改变对肿瘤环境中限制免疫功能的反应；和3：测试MyD88基因表达模式与患者结果不佳有关的假设。我们的研究设计结合了多种正宗胰腺肿瘤模型的CT引导的放射治疗，并使用 RT剂量和分馏范围。这些结合了独特的淘汰和测定，使我们得以在体外和体内识别髓样反应不同。我们对临床样本的分析使用高质量生物信息学方法使我们能够评估肿瘤环境对生物学反应的影响在患者样品中先天调节器。