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. " |