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，与公认的教条相反，在暴露于内源性免疫佐剂 MyD88 向巨噬细胞传递负信号，从而限制肿瘤控制我们证明，在免疫原性较差的肿瘤中，巨噬细胞会在放射治疗后重新连接。暴露于垂死的癌细胞，从而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的成熟。建议的目的是了解这种抑制发生的机制，确定对巨噬细胞抑制，并用它来识别对当前治疗反应不佳的患者群体我们认为，接触濒临死亡的细胞会重新连接巨噬细胞信号，从而使先天性改变。 MyD88的激活抑制局部肿瘤免疫本研究的具体目的是1：测试假设 MyD88 的缺失会阻止 NFKB 驱动的抗炎基因转录并导致 IRF3 驱动的 IFN 转录增加；2：检验通过 Mertk 介导的“重新布线”信号传导的假设巨噬细胞改变了肿瘤环境中对限制免疫功能的佐剂的反应；3：检验 MyD88 基因表达模式与患者不良预后相关的假设。设计结合了多个真实胰腺肿瘤模型的 CT 引导放射治疗，并使用一系列 RT 剂量和分级与独特的基因敲除和检测相结合，使我们能够我们使用高质量的临床样本分析来识别不同的骨髓反应。生物信息方法使我们能够评估肿瘤环境对生物反应的影响患者样本中的先天佐剂。