Targeting abnormal immunomechanics in the glioblastoma microenvironment to improve therapeutic response

针对胶质母细胞瘤微环境中的异常免疫力学以改善治疗反应

基本信息

批准号：
10452571
负责人：
Meenal Datta
金额：
$ 19.11万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452571
关键词：
3-Dimensional Adjuvant Bioinformatics Biological Biological Markers Biophysical Process Blood Blood Vessels Cell Compartmentation Cells Cephalic Data Enzyme-Linked Immunosorbent Assay Evaluation Excision Extracellular Matrix Feedback Fibrosis Flow Cytometry Genetic Genetic Models Glioblastoma Histology Hypoxia Immune Immunosuppression In Situ In Vitro Interruption Knockout Mice Losartan Malignant Neoplasms Maps Measurement Measures Mechanics Mediating Microglia Modeling Molecular Mus Myelogenous Myeloid Cells Neoplasms in Vascular Tissue Neurologic Dysfunctions Newly Diagnosed Operative Surgical Procedures Outcome Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Phenotype Production Quantitative Reverse Transcriptase PCR Radiation Regulation Reporter Research Resistance Role Slice Solid Solid Neoplasm Stress System Techniques Testing Training Tumor Immunity Tumor-associated macrophages Western Blotting Work angiogenesis base biomarker panel cell growth cell motility chemotherapy clinically translatable combinatorial confocal imaging drug efficacy fighting immune checkpoint blockade immune checkpoint blockers implantation improved in vivo insight intravital imaging mechanical force mouse model novel polarized cell resistance mechanism response response biomarker single cell sequencing standard of care targeted agent therapy outcome therapy resistant three dimensional cell culture tissue biomarkers translational approach treatment response tumor tumor microenvironment tumor progression

项目摘要

ABSTRACT Newly diagnosed glioblastoma (GBM) patients have a dismal survival of less than 2 years despite aggressive currently available treatments. Immune checkpoint blockade (ICB), which has revolutionized the treatment of other solid tumors, fails to enhance survival in the majority of GBM patients. The immunosuppressive, hypoxic, and extracellular matrix (ECM)-rich tumor microenvironment (TME) may be largely responsible for this poor response. One of the largest and most immunosuppressive components of the GBM TME is the myeloid cell compartment, consisting mainly of resident microglia and infiltrating tumor-associated macrophages (TAMs). These myeloid cells exist along a spectrum of phenotypes and functions ranging from pro-tumor (pro-fibrotic, angiogenic, and immunosuppressive) to anti-tumor (immune-supporting), and can dictate response to therapy. Furthermore, the GBM TME harbors “solid stress” – a mechanical force originating from cells and ECM – that can compress blood vessels, induce hypoxia and immunosuppression, and hinder anti-tumor immunity and drug efficacy. Here it is proposed that “immunomechanics” between pro-tumor myeloid cells and solid stress are reciprocally regulated in GBM, further promoting the abnormal TME and mediating resistance to ICB. This mechanopathological feedback loop will be evaluated by i) confirming the ability of myeloid cells to exert solid stress, and ii) the reciprocal ability of solid stress to promote pro-tumor myeloid cell phenotype and function (Aim 1). Next, this reciprocal regulation will be interrupted (genetically and pharmacologically) in murine GBM models to i) establish the causal roles of myeloid cells and solid stress in mediating immunosuppression in the TME, and ii) propose translatable ways to overcome them (Aim 2). Finally, myeloid targeting approaches will be combined with ICB to enhance therapeutic outcome, and both physical (solid stress) and biological biomarkers of treatment response will be identified (Aim 3). The results of the proposed work in this K22 application will: i) facilitate my transition to independence, ii) lay the groundwork for a successful R01 application within 3 years, and iii) revealing novel and targetable biophysical mechanisms underlying tumor progression and treatment resistance.

抽象的新诊断的胶质母细胞瘤（GBM）患者的生存率少于2年目的地侵略性免疫检查点封锁（ICB），已彻底改变其他实体瘤无法提高大多数GBM患者的生存率。免疫抑制，低氧，和细胞外基质（ECM） - 富含肿瘤微环境（TME）可能对这种贫困回复。 GBM TME最大，最免疫抑制的成分之一是髓样细胞室，主要由居民小胶质细胞和浸润肿瘤相关的巨噬细胞（TAM）组成。这些髓样细胞沿着表型和功能范围从促肿瘤（亲纤维化，，血管生成和免疫抑制）抗肿瘤（免疫支持），可以决定对治疗的反应。此外，GBM TME拥有“固体应力”（一种源自细胞和ECM的机械力） - 可以压缩血管，诱导缺氧和免疫抑制，并阻碍抗肿瘤免疫组织和药物效率。在这里提出，促肿瘤髓样细胞和固体应激之间的“免疫力学”是在GBM中相互调节，进一步促进了异常的TME并介导对ICB的耐药性。这机械病理反馈循环将通过i）确认髓样细胞的能力发挥固体的能力压力和ii）固体应力促进促肿瘤的髓样细胞表型和功能的互惠能力（AIM 1）。接下来，在鼠类GBM模型中，该互惠调节将被中断（遗传和药物） i）建立髓样细胞的因果作用，并在介导TME中的免疫抑制和固体应激中 ii）提案可以翻译来克服它们的方法（AIM 2）。最后，将组合髓样靶向方法与ICB一起增强热结局，以及治疗的身体应力和生物标志物将确定响应（AIM 3）。在此K22应用程序中拟议的工作的结果将：i）促进我的过渡到独立性，ii）为成功的R01申请奠定了基础，以及III）揭示了肿瘤进展和耐药性的新型和可靶向的生物物理机制。