Proj 3 - Targeting the Pro-tumorigenic Microenvironment

项目 3 - 针对促肿瘤微环境

• 批准号: 10017936
• 负责人: Yves A DeClerck
• 金额: $ 58.76万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017936
• 关键词: CCL2 gene; CXCL12 gene; Cell Communication; Cell Line; Cell Survival; Cells; Characteristics; Chemotactic Factors; Chronic; Clinical; Clinical Trials; Coculture Techniques; Cytotoxic Chemotherapy; Data; Diagnosis; Drug resistance; Environment; Epigenetic Process; Evolution; Exposure to; Fibroblasts; Growth; Human; IL8 gene; Immune; Immune Evasion; Immune signaling; Immunocompetent; Immunodeficient Mouse; Immunosuppression; Immunotherapy; Inflammation; Inflammation Mediators; Inflammatory; Interleukins; Investigation; Laboratories; MAPK3 gene; MYCN gene; Malignant Neoplasms; Mediating; Modeling; Mus; Neuroblastoma; Outcome; Pathway interactions; Patients; Phenotype; Production; Publishing; RNA; Recurrence; Resistance; STAT3 gene; Sampling; Secondary to; Signal Pathway; Source; Subgroup; Testing; Therapeutic; Therapeutic Agents; Transcript; Translating; Treatment Efficacy; Tumor-associated macrophages; VEGFA gene; anti-PD1 therapy; base; chemokine; chemotherapy; combinatorial; cytokine; defined contribution; disorder risk; early phase clinical trial; high dimensionality; high risk; immune activation; immune checkpoint; improved; in vivo; inhibitor/antagonist; macrophage; mesenchymal stromal cell; neoplastic cell; neuroblastoma cell; novel therapeutics; outcome forecast; paracrine; pre-clinical; prevent; receptor; recruit; response; targeted agent; targeted treatment; therapeutic evaluation; therapy resistant; tool; transcriptome; treatment response; tumor; tumor microenvironment; tumorigenic

SUMMARY/ABSTRACT The overall objective of Project 4 is to discover and exploit extrinsic mechanisms of therapy resistance by focusing on the contribution of tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs) in the tumor microenvironment (TME). Our overarching hypothesis is that TAMs and TAFs cooperate in creating a favorable tumorigenic environment that ultimately leads to the emergence of therapeutic resistance and immune escape in NB. We also postulate that as tumors are treated, the TME is altered in its composition and function to become increasingly favorable to therapeutic resistance. This hypothesis is based on published and preliminary data from our group demonstrating that TAMs and TAFs are abundantly present in an inflammatory subtype of NB at diagnosis associated with a high risk of recurrence and extremely poor prognosis. We also have evidence that TAMs and TAFs when exposed to tumor cells stimulate their proliferation, survival and drug-resistance via the paracrine production of pro-tumorigenic cytokines and chemokines that activate in tumor cells signaling pathways such as STAT3 and ERK. Our project has 3 aims. Aim 1, will examine mechanisms of cooperation between TAMs and TAFs, testing the hypothesis that in MYCN amplified tumors that do not produce the TAM chemoattractant CCL-2/MCP-1, TAFs are a source of this chemokine. We will also examine the contribution of cytokines and chemokines generated in co-culture of TAMs, TAFs and NB cells and the signaling pathways they activate in NB cells leading to increased proliferation and survival. Aim 2, will examine changes in the TME landscape secondary to chemotherapy in syngeneic murine NB models (with Project 2) and validate the data in patient tumor samples obtained via Core B. By examining changes in the transcriptome that occur in NB cells chronically exposed to TAM/TAF and their potential epigenetic origin (with Project 3), aim 2 will also identify vulnerabilities to prevent resistance to chemotherapy or targeted therapy (with Project 1). Aim 3, will then translate these discoveries in pre-clinical tumor models. We will test the therapeutic efficacy of the most promising agents targeting TAFs, TAMs, or pathways they activate in tumor cells in combination with chemotherapy or immunotherapy (with Project 5), using human NB lines and patient-derived xenotransplants in immunodeficient mice as well as murine cell lines in immunocompetent mice (with Project 2), The most effective agent(s) will then be proposed for early phase clinical trials to the NANT (Core B). Thus Project 4 brings a unique contribution to the overall objective of this PPG through its focus on the TME and on non-autonomous mechanisms leading towards therapeutic resistance and immune escape.

摘要/摘要 项目4的总体目标是通过发现和利用通过 专注于肿瘤相关巨噬细胞（TAM）和肿瘤相关的成纤维细胞的贡献 （TAF）在肿瘤微环境（TME）中。我们的总体假设是TAM和TAF合作 在创造有利的肿瘤环境中，最终导致治疗的出现 NB中的抗性和免疫逃脱。我们还假设，随着肿瘤的治疗，TME在其中被改变 组成和功能越来越有利于治疗性抗性。该假设是基于 关于我们小组的已发布和初步数据，证明TAM和TAF大量存在 在与高复发风险相关的NB炎症亚型中 预后。我们还有证据表明，暴露于肿瘤细胞时TAM和TAF刺激其 促氧化物细胞因子的旁分泌产生和抗药性，生存和抗药性 激活肿瘤细胞信号通路（例如STAT3和ERK）的趋化因子。我们的项目有3个目标。 AIM 1将检查TAMS和TAF之间合作的机制，并检验以下假设。 MYCN放大的肿瘤不产生TAM趋化剂CCL-2/MCP-1，TAF是一个来源 这个趋化因子。我们还将研究在共同培养中产生的细胞因子和趋化因子的贡献 TAM，TAF和NB细胞以及它们在NB细胞中激活的信号通路导致增加 增殖和生存。 AIM 2将检查继发于化学疗法的TME景观的变化 Syngeneic Murine NB模型（带有项目2），并验证通过核心获得的患者肿瘤样品中的数据 B.通过检查NB细胞中发生的转录组的变化，该细胞长期暴露于TAM/TAF和 它们的潜在表观遗传学起源（与项目3一起），AIM 2还将确定防止抵抗的脆弱性 化学疗法或有针对性的治疗（项目1）。 AIM 3，然后将这些发现转化为临床前 肿瘤模型。我们将测试针对TAF，TAM或 它们与化学疗法或免疫疗法结合（项目5），在肿瘤细胞中激活的途径， 在免疫缺陷小鼠和鼠细胞系中使用人NB线和患者衍生的异种移植剂 在免疫能力的小鼠（带有项目2）中，将提出最有效的药物的早期阶段 Nant的临床试验（Core B）。因此，项目4为总体目标带来了独特的贡献 PPG通过其专注于TME和导致治疗的非自主机制 抵抗和免疫逃脱。