O28 Myeloma Cell Survival and Importance of Crosstalk between Notch1-Jagged2 and CD28-B7 learn more pathways in Dendritic Cells Chandana Koorella 1 , Jayakumar Nair1, Sanjay Bansal1, Louise Carlson1, Pushpankur Ghoshal2, Kelvin Lee1 1 Department Of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA, 2 Department Of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Multiple myeloma is a neoplasm of bone marrow resident plasma cells characterized by a critical interaction between myeloma cells and bone marrow stromal cells, which produce IL-6, supporting myeloma cell survival. However, see more the

molecular and cellular components involved in myeloma induced IL-6 production remain largely uncharacterized. At the cellular level, dendritic cells (DC) in the bone marrow microenvironment and at the molecular level the CD28-B7 and Notch1-Jagged2 pathways were separately implicated by us in myeloma induced IL-6 production. While Notch signaling leading to IL-6 production in DC is well understood, the mechanism of “backsignaling” Ruxolitinib via B7, a ligand with a short cytoplasmic

tail, is largely uncharacterized. To gain insight into B7 signaling, DC were stimulated with CD28Ig in the presence or absence of an inhibitor of Notch signaling, gamma secretase inhibitor (GSI). DC treated with CD28Ig alone produced significantly higher levels of IL-6 when compared to DC treated with CD28Ig and GSI. GSI specifically targeted Notch signaling as observed by decreased expression of Notch gene targets: Hes1 and Deltex4. Also, decreased IL-6 levels in presence of GSI were not due to the decrease in B7 expression on DC. To specifically implicate the importance of Notch1 and Jagged2,

we blocked them using antibodies and observed a similar decrease in IL-6 production upon blocking Notch1 signaling. Our results suggest that CD28 mediated IL-6 production is dependent on Notch1 signaling and crosstalk between the Notch1-Jagged2 and CD28-B7 pathways leads to IL-6 production by DC. We are examining a potential direct/ indirect mechanism of crosstalk in myeloma induced IL-6 production. Targeting IL-6 induced by crosstalk between these two pathways prompts not only clinical evaluation SB-3CT to improve MM patient outcome but also extends to advancing knowledge in T-cell biology. O29 Interleukin-18-Dependent Genes of Highly Metastatic Human Melanoma Olatz Crende 1 , Marianna Sabatino2, Maria Valcarcel3, Ena Wang2, Francesco M. Marincola2, Fernando Vidal-Vanaclocha1 1 Department of Cell Biology and Histology, Basque Country University School of Medicine, Leioa, Bizkaia, Spain, 2 Department of Transfusion Medicine, Infectious Disease and Immunogenetics Section, National Institutes of Health, Bethesda, MD, USA, 3 Pharmakine SL, Bizkaia Technology Park, Derio, Bizkaia, Spain Because immune-stimulating effects of interleukin (IL)-18 have anti-neoplastic properties, IL-18 has been proposed as an adjuvant therapy against cancer.