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（由应用程序提供）：小胶质细胞是中枢神经系统独有的免疫胶体类型，在免疫监视，吞噬作用和神经炎症中起关键作用。小胶质细胞位于脑实质中，并有助于维持体内稳态免疫抑制环境，部分原因是它们的CX3CR1受体的表达，而fnavcr1受体（FKN/CX3CL1）是唯一已知的配体。 FKN始终由神经元和星形胶质细胞表达，从而导致小胶质细胞激活2。但是，我们发现在存在髓母细胞瘤（MB）的情况下，由于肿瘤细胞表达FKN，FKN信号传导改变了，因此小胶质细胞起着主要作用，因为吞噬细胞表现出与活性表型一致的某些上调的细胞表面制造商一致的上调细胞表面制造商。这与其他报道形成对比，表明浸润单核细胞在神经元破坏中起主要作用，并促进促炎环境3，4。由于小胶质细胞在肿瘤微环境中的精确作用尚未阐明，因此还保证了进一步的投资。为了打击许多癌症类型，尤其是实体瘤，必须采用新的和创新的癌症治疗方法。 Available evidence now favors the view that physical immunosurgery by members of the innate and adaptive immunosurgery 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 immunosurveillance within the CNS is further complicated by the presence of the血脑屏障（BBB）。 MB是儿科环境中最常见的恶性中枢神经系统肿瘤，占小儿中枢神经系统恶性肿瘤的20％。它是WHO级IV原始神经皮质肿瘤（PNET），它在小脑中发展，经常侵入包括第四脑室和脑茎7在内的周围结构。尽管治疗方式和更重要的是，治疗后认知监测的管理改善了总体结果，但生存患者仍然患有认知后遗症，包括但不限于言语能力，感知组织，社会感知和精神运动技能8。因此，需要新的治疗选择，以避免与中枢神经系统外科手术，化学治疗和放射疗法方法有关的直接毒性。了解先天和适应性免疫系统的肿瘤逃脱检测和/或消除的机制对于开发新的基于免疫的治疗至关重要。 FKN信号传导可能会提供关键信号，从而导致中枢神经系统内的小胶质细胞介导的免疫抑制。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关键的见解，这将导致更有效的免疫治疗方法。