Targeted STAT3 inhibition impairs MDSC mobilization and recruitment in glioblastoma

靶向 STAT3 抑制损害胶质母细胞瘤中 MDSC 的动员和募集

• 批准号: 10439442
• 负责人: Christina Anna Elizabeth Von Roemeling
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2023-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439442
• 关键词: Advocate; Antitumor Response; Automobile Driving; Biological Factors; Biological Response Modifiers; Blood Circulation; Bone Marrow; Bone Marrow Neoplasms; Brain; Brain Neoplasms; Cells; Chemotherapy and/or radiation; Data; Detection; Distal; Environment; Equilibrium; Excision; Flow Cytometry; Fostering; Foundations; Glioblastoma; Glioma; Immune; Immunologics; Immunosuppression; Immunotherapy; Impairment; Infiltration; Inflammatory; Light; Malignant Glioma; Malignant Neoplasms; Marrow; Mediating; Microscopy; Modality; Modeling; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neutrophil Infiltration; Operative Surgical Procedures; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Process; Production; Refractory; Resistance; Resolution; Role; Stat3 protein; Techniques; Therapeutic; Tumor Burden; Tyrosine; Work; anti-cancer; beta-Chemokines; cancer cell; cancer therapy; cell transformation; chemokine receptor; design; experimental study; granulocyte; immune checkpoint blockade; immunogenic; inhibitor; macrophage; mouse model; neoplastic cell; neutrophil; novel; novel therapeutics; pre-clinical; prevent; progenitor; prognostic indicator; recruit; response; side effect; single-cell RNA sequencing; small molecule; small molecule inhibitor; standard of care; stem; synergism; targeted treatment; trafficking; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenesis

Project Summary/Abstract Glioblastoma (GBM) is a universally lethal tumor for which standard of care has not changed in over 10 years. Unfortunately, immunotherapies that produce durable responses in other aggressive cancers have failed against GBM. One major obstacle limiting their efficacy is the opposing immunosuppressive actions levied by myeloid- derived suppressor cells within the tumor microenvironment. STAT3 expression is enriched in GBM, and is a negative prognostic indicator of survival. Moreover, active STAT3 (phosphorylated at tyrosine 705, P-STAT3) is a specific marker of MDSC cells, and plays an important role in their phenotypic polarization. While the existing evidence strongly justifies the role of STAT3 as a driver of tumorigenesis and practical target for anti-cancer therapy, the functional role of STAT3 in distal MDSC immune cells remains unresolved. In this proposal I provide preliminary evidence that supports that STAT3 is activated in polymorphonuclear MDSC (PMN-MDSC) cells within the bone marrow of tumor bearing syngeneic mice, and that pharmacologic inhibition with the small molecule drug LLL12B greatly reduces the number of PMN-MDSCs that enter systemic circulation. These findings highlight a critically important role for STAT3 in the mobilization of PMN-MDSCs in response to tumor presence, as well as a novel mechanism of anti-tumor action for LLL12B and other specific inhibitors of STAT3. Implementing a number of advanced techniques including high resolution microscopy, flow cytometry, and single cell RNA sequencing, I outline experiments utilizing syngeneic models of GBM designed to 1) characterize which immune cells within GBM express P-STAT3, 2) determine whether this activation occurs locally within the tumor or peripherally, and 3) identify the mechanistic role of STAT3 in governing PMN-MDSC trafficking. I hypothesize that targeted inhibition of STAT3 will block PMN-MDSC mobilization from the bone marrow, preventing them from accumulating within GBM tumors. This ultimately will shift the immunogenic balance from immune- suppressive to pro-inflammatory, allowing for immune mediated detection and killing of cancer cells.

项目总结/摘要 胶质母细胞瘤（GBM）是一种普遍致命的肿瘤，其护理标准在10多年来没有改变。 不幸的是，在其他侵袭性癌症中产生持久反应的免疫疗法未能对抗 GBM。限制其疗效的一个主要障碍是髓系细胞引起的相反的免疫抑制作用， 肿瘤微环境中的衍生抑制细胞。STAT 3表达在GBM中富集，并且是一种免疫调节因子。 生存率的阴性预后指标。此外，活化的STAT 3（在酪氨酸705处磷酸化，P-STAT 3）是 MDSC细胞的特异性标记物，并在其表型极化中起重要作用。而现有的 证据有力地证明了STAT 3作为肿瘤发生的驱动因素和抗癌的实际靶点的作用 然而，尽管STAT 3在远端MDSC免疫细胞中的功能性作用尚未得到解决。在这份提案中，我提出 支持STAT 3在多形核MDSC（PMN-MDSC）细胞中被激活的初步证据 在携带肿瘤的同系小鼠的骨髓中， 分子药物LLL 12 B大大减少了进入体循环的PMN-MDSC的数量。这些 研究结果强调了STAT 3在PMN-MDSC动员中的关键作用， 的存在，以及LLL 12 B和STAT 3的其他特异性抑制剂的抗肿瘤作用的新机制。 实施了许多先进的技术，包括高分辨率显微镜，流式细胞术，和单 细胞RNA测序，我概述了利用GBM的同基因模型的实验，其设计用于1）表征， GBM内的免疫细胞表达P-STAT 3，2）确定这种激活是否局部发生在肿瘤内 或外周，和3）确定STAT 3在管理PMN-MDSC贩运的机制作用。我假设 STAT 3的靶向抑制将阻断PMN-MDSC从骨髓中的动员， 在胶质母细胞瘤中积累。这最终将改变免疫原性平衡，从免疫- 抑制性至促炎性，允许免疫介导的检测和杀死癌细胞。