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 的总体目标是通过以下方式发现和利用治疗抵抗的外在机制： 重点关注肿瘤相关巨噬细胞（TAM）和肿瘤相关成纤维细胞的贡献 （TAF）在肿瘤微环境（TME）中。我们的首要假设是 TAM 和 TAF 合作 创造有利的致瘤环境，最终导致治疗药物的出现 NB 中的耐药性和免疫逃逸。我们还假设，随着肿瘤的治疗，TME 的功能也会发生改变。 成分和功能变得越来越有利于治疗耐药性。这个假设是基于 我们小组已发表的初步数据表明 TAM 和 TAF 大量存在 诊断时为 NB 炎症亚型，复发风险高且极差 预后。我们还有证据表明，TAM 和 TAF 在暴露于肿瘤细胞时会刺激它们 通过旁分泌促肿瘤细胞因子的增殖、存活和耐药性 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。 目标 1，将研究 TAM 和 TAF 之间的合作机制，检验以下假设： MYCN 扩增的肿瘤不产生 TAM 趋化剂 CCL-2/MCP-1，TAF 是 TAM 趋化剂的来源 这种趋化因子。我们还将检查共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。目标 2，将检查继发于化疗的 TME 景观的变化 同基因小鼠 NB 模型（使用项目 2）并验证通过 Core 获得的患者肿瘤样本中的数据 B. 通过检查长期暴露于 TAM/TAF 的 NB 细胞中发生的转录组变化 它们潜在的表观遗传起源（与项目 3 一起），目标 2 还将识别脆弱性，以防止耐药性 化疗或靶向治疗（项目 1）。目标 3，然后将这些发现转化为临床前 肿瘤模型。我们将测试最有前途的靶向 TAF、TAM 或 与化疗或免疫疗法（项目 5）相结合，它们在肿瘤细胞中激活的途径， 在免疫缺陷小鼠以及鼠细胞系中使用人类 NB 系和患者来源的异种移植物 在免疫功能正常的小鼠（项目 2）中，最有效的药物将被建议用于早期阶段 NANT（核心 B）的临床试验。因此，项目 4 对该项目的总体目标做出了独特的贡献 PPG 通过专注于 TME 和非自主机制来实现治疗 抵抗力和免疫逃逸。