Targeting Syk to enhance anti-tumor immune responses in neuroblastoma

靶向 Syk 增强神经母细胞瘤的抗肿瘤免疫反应

• 批准号: 10455584
• 负责人: Shweta Joshi
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455584
• 关键词: Bone Marrow; CD8-Positive T-Lymphocytes; Cell Line; Cells; Cephalic; Child; Childhood; Childhood Extracranial Solid Tumor; Clinical; Combined Modality Therapy; Data; Disease; Failure; Genetic; Genetic Transcription; Goals; Histology; Hypoxia Inducible Factor; Immune; Immune checkpoint inhibitor; Immunization; Immunologic Memory; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; Implant; In Vitro; Infiltration; Inflammatory; Interleukin-10; Knockout Mice; Knowledge; Laboratories; MYCN gene; Malignant Childhood Neoplasm; Mediating; Molecular; Monoclonal Antibodies; Mus; Mutation; Myelogenous; Neoplasm Metastasis; Neuroblastoma; Oncogenes; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Phosphotransferases; Ploidies; Population; Primary Neoplasm; Prognosis; Progressive Disease; Radiation therapy; Regulation; Research; Resistance; Role; SYK gene; Signal Pathway; Signal Transduction; Solid Neoplasm; T cell response; T-Lymphocyte; Testing; Transforming Growth Factor beta; Treatment Failure; Tumor-associated macrophages; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; adaptive immune response; adaptive immunity; anti-PD-1; anti-PD-L1; anti-tumor immune response; arginase; base; checkpoint therapy; combinatorial; cytotoxic; cytotoxic CD8 T cells; driving force; enhancer binding protein; high risk; high risk population; hypoxia inducible factor 1; immune checkpoint blockade; improved; improved outcome; macrophage; mouse model; neoplastic cell; novel; novel therapeutics; patient stratification; pediatric patients; predict responsiveness; programs; recruit; standard care; standard of care; transcriptomics; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT: There is critical need to develop novel therapies for neuroblastoma (NB). NB is the most common extracranial pediatric cancer and even after aggressive multimodal treatments, high-risk patients succumb to progressive disease. One of the reasons underlying failure of these therapies in NB is the highly immunosuppressive tumor microenvironment generated by tumor associated macrophages (TAMs) that inhibit both innate and adaptive immune responses. The long-term goal is to better understand the signaling mechanisms by which TAMs mediate tumor immunosuppression and inhibit anti-tumor immune responses in high-risk NB. The overall objectives in this particular application are 1) to determine the role of spleen tyrosine kinase (Syk) in macrophage (MΦ)-mediated immunosuppression in MYCN and non-MYCN amplified (MYCN-NA) NB tumors and 2) to test whether Syk inhibitors combined with immune checkpoint inhibitors or standard care of therapies can improve anti-tumor immune responses in NB. The central hypothesis motivating this research is that Syk in immunosuppressive TAMs inhibits T cell responses and promotes resistance to checkpoint inhibitors in mouse models of NB. This hypothesis has been formulated on the basis of evidences generated in our laboratory utilizing Syk inhibitors and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which Syk promote immunosuppression in MYCN and non- MYCN amplified (MYCN-NA) tumors has the potential to identify an immunological signature which will predict responsiveness to Syk inhibitors in NB tumors driven by a Syk-MΦ-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: in Aim 1, we will evaluate the effects of myeloid Syk deficiency on NB tumor microenvironment and infiltrating immune populations. In Aim 2, we will investigate molecular mechanisms by which Syk regulate immunosuppressive MΦ polarization in MYCN and MYCN-NA NB tumors. In Aim 3, we will determine whether Syk inhibitors in combination with checkpoint blockade or current therapies can augment anti-tumor immune responses in NB. The significance of our proposal lies in our capacity to develop novel combinatorial therapy of Syk inhibitors with immunotherapy or standard of care therapies that is more effective than current therapies in NB.

项目总结/摘要： 迫切需要开发用于神经母细胞瘤（NB）的新疗法。NB是最常见的颅外 即使在积极的多模式治疗后，高危患者也会死于进行性癌症。 疾病这些治疗在NB中失败的潜在原因之一是高度免疫抑制的肿瘤 肿瘤相关巨噬细胞（TAM）产生的微环境，抑制先天性和适应性 免疫反应。长期目标是更好地了解TAM的信号机制， 介导肿瘤免疫抑制并抑制高危NB中的抗肿瘤免疫应答。整体 该特定应用的目的是1）确定脾酪氨酸激酶（Syk）在 MYCN和非MYCN扩增（MYCN-NA）NB肿瘤中巨噬细胞（MΦ）介导的免疫抑制 和2）测试Syk抑制剂是否与免疫检查点抑制剂或标准治疗组合 可提高NB的抗肿瘤免疫应答。推动这项研究的中心假设是， 免疫抑制性TAM抑制小鼠T细胞应答并促进对检查点抑制剂的抗性 NB的模型这一假设是根据我们实验室的证据提出的 利用Syk抑制剂和Syk-/-小鼠模型用于免疫肿瘤学。拟议研究的理由 了解Syk促进MYCN和非MYCN免疫抑制的分子机制 MYCN扩增（MYCN-NA）肿瘤有可能识别一种免疫学特征， 由Syk-MΦ依赖性免疫抑制性TME驱动的NB肿瘤中对Syk抑制剂的反应性。 在强有力的初步数据的指导下，这一假设将通过追求三个具体目标来检验：在目标1中，我们 将评估髓系Syk缺陷对NB肿瘤微环境和浸润性免疫的影响， 人口。在目标2中，我们将研究Syk调节免疫抑制的分子机制， MYCN和MYCN-NA NB肿瘤中的MΦ极化。在目标3中，我们将确定Syk抑制剂是否在 与检查点阻断或当前疗法的组合可以增强NB中的抗肿瘤免疫应答。 我们的建议的意义在于我们有能力开发新的Syk抑制剂组合疗法 免疫疗法或标准护理疗法比NB中的当前疗法更有效。