Cnsc-01. the role of serotonergic receptor, htr2b, on myeloid derived suppressor cells in the brain metastatic environment

Abstract In the United States, greater than 12% of cancer patients develop brain metastases (br-mets) and median survival remains an abysmal 4-6 months. Throughout the metastatic cascade, tumor cells attract and reprogram stromal cells, such as myeloid derived suppressor cells (MDSCs), which support cancer growth by promoting tissue remodeling, EMT, invasion, immunosuppression, angiogenesis. Once tumor cells have breached the brain’s CNS defenses, infiltrating immune cells can penetrate the glia limitans and enter the CNS parenchyma to help establish the brain metastatic niche. However, there is scant understanding of MDSC’s contribution to the brain metastatic microenvironment. The brain metastatic environment is particularly unique because CNS-resident cells such as microglia, astrocytes, choroid plexus, and neurons function as local mediators to alter invading immune cell plasticity and differentiation. We have demonstrated that MDSCs in the brain microenvironment respond to the neurotransmitter serotonin, upregulate the serotonergic receptor, HTR2B, resulting in increase pNF-κB and its associated signaling genes (IL-6, IL-1B, COX2, CXCL2, NOS2). Furthermore, HTR2B knockdown in MDSCs alters downregulates expression of pNF-κB signaling genes. Additionally, MDSCs in this environment support tumor cell proliferation while hindering their acquisition of neuronal traits. A better understanding of the role of HTR2B in brain metastasis may allow us to develop new treatment strategies for patients of this devastating disease.