Loss of Fractalkine Signaling Affects CNS Tumor Growth via Microglia Interactions

Fractalkine 信号丢失通过小胶质细胞相互作用影响中枢神经系统肿瘤生长

基本信息

批准号：
9071296
负责人：
Rodney Dixon Dorand
金额：
$ 2.96万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-12 至 2018-05-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9071296
关键词：
Accounting Affect Aftercare Alternative Therapies Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen-Presenting Cells Antigens Astrocytes Beds Binding Biopsy Blood - brain barrier anatomy Brain CX3CL1 gene Cell surface Cells Central Nervous System Neoplasms Cerebellum Childhood Cognitive Coupled Detection Development Environment Experimental Autoimmune Encephalomyelitis Fourth ventricle structure Fractalkine Functional disorder Goals Human Immune Immune system Immunologic Surveillance Immunophenotyping Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Implant In Vitro Inflammatory Invaded Investigation Kinetics Knowledge Laser Scanning Microscopy Lead Ligands Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Membrane Membrane Proteins Microglia Mitotic Modality Modeling Molecular Monitor Morbidity - disease rate Mus Mutation Myelogenous Myeloid Cells Neoplasm Metastasis Neuraxis Neurocognitive Neurons Operative Surgical Procedures Outcome Parkinson Disease Pathologic Patients Phagocytes Phagocytosis Phenotype Physiological Play Population Primitive Neuroectodermal Tumor Process Production RNA Interference Radiation therapy Radiosurgery Reaction Recruitment Activity Reporter Reporting Research Personnel Role SHH gene Scientist Signal Transduction Signaling Molecule Slice Social Perception Solid Neoplasm Structure Subgroup T cell therapy T-Cell Activation T-Lymphocyte TP53 gene Therapeutic Time Toxic effect Tumor Burden Tumor Cell Line Tumor Escape base brain parenchyma cancer therapy cancer type cell type chemokine combat cytokine improved in vivo innovation insight macrophage medulloblastoma member monocyte neoplasm immunotherapy neoplastic cell neuropathology novel outcome forecast perceptual organization protein expression public health relevance receptor response smoothened signaling pathway tumor tumor growth tumor microenvironment two-photon

项目摘要

DESCRIPTION (provided by applicant): Microglia is an immune cell type unique to the CNS that plays a pivotal role in immune surveillance, phagocytosis, and neuroinflammation1. Microglia resides in the brain parenchyma and help maintain the homeostatic immunosuppressive environment partially due to their expression of CX3CR1 receptor for which Fractalkine (FKN/CX3CL1) is the only known ligand. FKN is constitutively expressed by neurons and astrocytes leading to tonic inhibition of microglial activation2. However, we have found that in the presence of medulloblastoma (MB), FKN signaling is altered due to expression of FKN by tumor cells, and as such microglia play a major role as phagocytes displaying certain up-regulated cell surface makers consistent with an activated phenotype. This contrasts with other reports showing that infiltrating monocytes play the major role in neuronal destruction and promote a pro-inflammatory environment3, 4. Because the precise role of microglia in the tumor microenvironment has yet to be elucidated, further investigation is warranted. New and innovative approaches to cancer treatment are necessary to combat many cancer types, especially solid tumors. Available evidence now favors the view that physiological immune surveillance by members of the innate and adaptive immune systems play an essential role in suppressing tumor development in vivo, and that deficiency in this surveillance mechanism favors tumor development and metastasis formation5, 6. Additional challenges exist when solid tumors develop within the central nervous system (CNS), as immune surveillance within the CNS is further complicated by the presence of the blood brain barrier (BBB). MB is the most common malignant CNS neoplasm in the pediatric setting, accounting for 20% of pediatric CNS malignancies overall. It is a WHO-Grade IV primitive neuroectodermal tumor (PNET) that develops in the cerebellum and often invades into surrounding structures including the fourth ventricle and the brain stem7. While treatment modalities and, more importantly, management of post treatment cognitive monitoring have improved overall outcomes, surviving patients still suffer cognitive sequelae including but not limited to verbal ability, perceptual organization, social perception, and psychomotor skills8. Hence there is a need for new treatment options that avoid direct toxicities associated with CNS surgical, chemotherapeutic, and radiotherapy approaches. Understanding the mechanisms by which tumors escape detection and/or elimination by the innate and adaptive immune systems is imperative for developing new immune based therapeutics. FKN signaling may provide the key signal leading to microglia-mediated immune suppression within the CNS. Therefore, characterization of FKN signaling in the MB microenvironment will provide critical insight into the immunosuppressive capacity of tumors that will lead to more effective immunotherapeutic approaches.

描述（由申请人提供）：小胶质细胞是中枢神经系统特有的一种免疫细胞类型，在免疫监视、吞噬作用和神经炎症中发挥着关键作用。小胶质细胞存在于脑实质中，部分由于其表达CX3CR1 受体，Fractalkine (FKN/CX3CL1) 是唯一已知的 FKN 组成型表达配体。然而，我们发现，在髓母细胞瘤 (MB) 存在的情况下，FKN 信号传导因肿瘤细胞表达 FKN 而改变，因此小胶质细胞作为吞噬细胞发挥着重要作用。显示出与激活表型一致的某些上调的细胞表面标记，这与其他报告形成鲜明对比，其他报告表明浸润单核细胞在神经元破坏和促进促炎环境中发挥主要作用3、4。由于小胶质细胞在肿瘤微环境中的确切作用尚未阐明，因此需要进一步研究癌症治疗的新方法，以对抗许多癌症类型，特别是实体瘤，目前的现有证据支持生理免疫监视的观点。先天性和适应性免疫系统成员的监测在抑制体内肿瘤发展方面发挥着重要作用，这种监测机制的缺陷有利于肿瘤发展和转移形成5, 6。当实体瘤在中枢神经系统 (CNS) 内发展时，还存在其他挑战），作为血脑屏障 (BBB) 的存在使 CNS 内的免疫监视变得更加复杂，MB 是儿科最常见的恶性 CNS 肿瘤，占儿科 CNS 恶性肿瘤的 20%，属于 WHO IV 级。原始神经外胚层肿瘤 (PNET) 在小脑中发生，经常侵入周围结构，包括第四脑室和脑干7。尽管监测改善了总体结果，幸存的患者仍然遭受认知后遗症，包括但不限于语言能力、知觉组织、社会感知和精神运动技能8，因此需要新的治疗方案来避免与中枢神经系统手术、化疗、化疗相关的直接毒性。了解肿瘤逃避先天性和适应性免疫系统检测和/或消除的机制对于开发基于 FKN 信号的新免疫疗法至关重要，可能会提供导致小胶质细胞介导的免疫抑制的关键信号。因此，MB 微环境中 FKN 信号传导的表征将为肿瘤的免疫抑制能力提供重要的见解，从而带来更有效的免疫治疗方法。