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.

项目摘要/摘要胶质母细胞瘤是IV级弥漫性星形细胞瘤，是成人脑癌的最致命，最常见的形式。护理标准将生存延长了大约1-18个月，而较早的收益最差患者（> 70年）。新形式的基于免疫的疗法，包括免疫抑制剂（ICI），可能会转动原发性和复发性胶质母细胞瘤治疗的角落。不幸的是，到目前为止尚未显示临床试验这些患者的生存或免疫参与度的主要好处。最近的发现表明神经胶质瘤藏有多重且互动的细胞来源，这些抑制是该死的ICI引起的反应。这是一种解决方案，不仅是通过阻止CTLA-4和PD-等检查点来增强效应T细胞 1，但还针对胶质母细胞瘤的免疫抑制壁ches，其中最大的是神经胶质瘤 - 相关的小胶质细胞和巨噬细胞（GAM）。实际上，游戏是一个极具吸引力的目标，一直通过CSF1R抑制（PLX3397）在临床前和临床研究中耗尽。但是，这种方法产生了模型中的混合反应，患者没有反应。可能是重新编程游戏，但我们缺乏洞悉促进反肿瘤游戏的途径。因此，鉴定细胞和分子亲和反肿瘤的监管机构是解锁新的治疗途径的下一步。最近的工作由Kaech Lab通过 T细胞（Treg）浸润，增加了“助手” Th1细胞浸润，而小胶质细胞暴露于Th1细胞衍生的IFNG 将重新编程为抗原呈递（MHCII+），肿瘤 - 斑点（AXL+/MER+）状态；在音乐会上这些影响显着提高了生存率。该建议将调查游戏，尤其是大脑的方式居民小胶质细胞，以下假设是Treg特异性信号传导，获取和维持不同的功能状态在胶质母细胞瘤进展过程中维持促进肿瘤的GAM，而Th1 T细胞诱导肿瘤的GAM 在有效的ICI发起的响应中。提出了两个具体的目的来审问这一假设。第一个 AIM将采用单细胞空间转录组学来解决Tregs和Th1细胞是否为外部调节剂通过直接接触和/或秘书信号传导的GAM状态，以及这些相互作用轴是否存在人胶质母细胞瘤。第二个目标将定义固有的AXL/MER和相关途径调节GAM 状态“切换”。总而言之，这项工作将通过定义如何渗透来更好地告知GAM靶向干预措施 T细胞和GAM-内在信号通路协调了促肿瘤和抗肿瘤的动态生物学 GAM州。该应用程序概述了该申请的拟议培训计划，其中包括多样化和多学科研究心态，尖端和先进技术的培训以及发展更广泛的科学技能，例如协作和有效的沟通。概述的研究和培训该提案将使申请人为进行创新，严格和有影响力的研究做好准备。