Elucidating the distinct roles of T cell-polarized microglia in glioblastoma suppression and progression

阐明 T 细胞极化小胶质细胞在胶质母细胞瘤抑制和进展中的独特作用

基本信息

批准号：
10752583
负责人：
Lizmarie Garcia-Rivera
金额：
$ 4.02万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752583
关键词：
Address Adopted Adult Antigen Presentation Antitumor Response Architecture Biology Brain Brain Injuries CD4 Positive T Lymphocytes CSF1R gene CTLA4 blockade CTLA4 gene Cells Clinical Research Clinical Trials Collaborations Communication Cues Data Dependence Development Diffuse astrocytoma Environment Exposure to Failure Genetic Transcription Glioblastoma Glioma Human Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immune system Immunosuppression Immunotherapy Infiltration Inflammatory Infiltrate Inflammatory Response Interdisciplinary Study Intervention Ligands Long-Term Care Macrophage Malignant Neoplasms Malignant neoplasm of brain Mentorship Methods Microglia Modeling Molecular Mus Myeloid-derived suppressor cells Natural Immunity Nature Neuroglia Other Genetics Pathway interactions Patients Peripheral Phagocytes Phagocytosis Phase II Clinical Trials Physicians Population Receptor Protein-Tyrosine Kinases Recurrence Regulation Regulatory T-Lymphocyte Repression Research Role Scientist Shapes Signal Pathway Signal Transduction Source T cell infiltration T-Lymphocyte Techniques Th1 Cells Therapeutic Tissue Preservation Training Tumor Promotion Tumor Subtype Work anti-CTLA4 anti-tumor immune response checkpoint therapy effector T cell genetic approach innovation insight mouse genetics mouse model neuroinflammation novel novel therapeutics older patient patient engagement polarized cell preclinical study programmed cell death protein 1 programs receptor recruit response skills standard of care targeted treatment transcriptomics tumor tumor growth tumor microenvironment

项目摘要

Project Summary/Abstract Glioblastoma is a grade IV diffuse astrocytoma, the deadliest and most common form of adult brain cancer. Standard of care extends survival by approximately 1-18 months, with the poorest benefits being seen by elderly patients (>70yrs). New forms of immune-based therapies, including immune checkpoint inhibitors (ICI), may turn the corner in treatments for primary and recurrent glioblastoma. Unfortunately, no clinical trial so far has shown major benefits in either survival or immune engagement for these patients. Recent findings suggest that gliomas harbor multiple and intertwined cellular sources of immune suppression that dampen ICI-initiated responses. Thus, one solution may be to not only enhance effector T cells by blocking checkpoints such as CTLA-4 and PD- 1, but to also target the immune suppressive niches in glioblastoma, the largest of which is comprised of glioma- associated microglia and macrophages (GAMs). In fact, GAMs are a highly attractive target and have been depleted in pre-clinical and clinical studies via CSF1R inhibition (PLX3397). This approach, however, yielded mixed responses in models and no response in patients. Another path may be to reprogram GAMs, but we lack insights into the pathways that promote anti-tumor GAMs. Therefore, identifying the cellular and molecular regulators of pro- and anti-tumor GAM states is the next step in unlocking new therapeutic avenues. Recent work by the Kaech lab showed that CTLA-4 blockade in orthotopic mouse models of glioblastoma reduced regulatory T cell (Treg) infiltration, increased ‘helper’ Th1 cell infiltration, and microglia exposed to Th1 cell-derived IFNg were reprogrammed into an antigen presenting (MHCII+), tumor-phagocytosing (AXL+/MER+) state; in concert, these effects significantly increased survival. This proposal will investigate how GAMs, especially the brain resident microglia, acquire and maintain distinct functional states with the hypothesis that Treg-specific signaling sustains tumor-promoting GAMs during glioblastoma progression while Th1 T cells induce tumor-killing GAMs during an effective ICI-initiated response. Two specific aims are proposed to interrogate this hypothesis. The first aim will employ single-cell spatial transcriptomics to address whether Tregs and Th1 cells are extrinsic regulators of GAM states through direct contact and/or secretory signaling, and whether these interaction axes exist in human glioblastoma. The second aim will define the intrinsic AXL/MER and related pathways regulating GAM state ‘switching’. In summary, this work will better inform GAM-targeting interventions by defining how infiltrating T cells and GAM-intrinsic signaling pathways coordinate the dynamic biology underlying pro- and anti-tumor GAM states. This application outlines the applicant’s proposed training plan, which includes diverse and multidisciplinary research mentorship, training in cutting-edge and advanced techniques, and development of broader scientific skills such as collaboration and effective communication. The research and training outlined in this proposal will prepare the applicant to conduct innovative, rigorous, and impactful research.

项目概要/摘要胶质母细胞瘤是一种 IV 级弥漫性星形细胞瘤，是成人脑癌中最致命和最常见的形式。标准护理可将生存期延长约 1-18 个月，其中老年人受益最差包括免疫检查点抑制剂 (ICI) 在内的新型免疫疗法可能会转向患者（>70 岁）。不幸的是，迄今为止还没有临床试验表明它是原发性和复发性胶质母细胞瘤治疗的关键。最近的研究结果表明，神经胶质瘤对这些患者的生存或免疫参与有重大益处。存在多种相互交织的免疫抑制细胞来源，抑制 ICI 引发的反应。因此，一种解决方案可能不仅是通过阻断 CTLA-4 和 PD-等检查点来增强效应 T 细胞， 1，但也针对胶质母细胞瘤中的免疫抑制生态位，其中最大的是胶质瘤- 事实上，GAM 是一个非常有吸引力的目标，并且已经成为人们关注的焦点。然而，在临床前和临床研究中，通过 CSF1R 抑制 (PLX3397) 耗尽了该药物。模型中反应不一，患者没有反应另一种途径可能是重新编程 GAM，但我们缺乏。深入了解促进抗肿瘤 GAM 的途径，从而识别细胞和分子。亲肿瘤和抗肿瘤 GAM 状态的监管者是解锁新治疗途径的下一步。 Kaech 实验室的研究表明，在胶质母细胞瘤原位小鼠模型中阻断 CTLA-4 会降低调节作用 T 细胞 (Treg) 浸润、“辅助”Th1 细胞浸润增加以及小胶质细胞暴露于 Th1 细胞衍生的 IFNg 被重新编程为抗原呈递（MHCII+）、肿瘤吞噬（AXL+/MER+）状态；这些效应显着提高了 GAM 的存活率，尤其是大脑。驻留小胶质细胞，获得并维持不同的功能状态，假设 Treg 特异性信号传导在胶质母细胞瘤进展过程中维持促肿瘤 GAM，而 Th1 T 细胞诱导肿瘤杀伤 GAM 在 ICI 发起的有效应对过程中，提出了两个具体目标来质疑这一假设。目标将采用单细胞空间转录组学来解决 Tregs 和 Th1 细胞是否是外在调节因子通过直接接触和/或分泌信号传导的 GAM 状态，以及这些相互作用轴是否存在于第二个目标将定义内在的 AXL/MER 和调节 GAM 的相关途径。总之，这项工作将通过定义渗透方式更好地为针对 GAM 的干预措施提供信息。 T 细胞和 GAM 内在信号通路协调促肿瘤和抗肿瘤的动态生物学 GAM 指出，该申请概述了申请人提出的培训计划，其中包括多样化和多学科研究指导、尖端和先进技术培训以及开发更广泛的科学技能，例如协作和有效沟通。该提案将使申请人做好准备进行创新、严谨和有影响力的研究。