Targeting Syndecan-1, a molecule implicated in the process of vasculogenic mimicry, enhances the therapeutic efficacy of the L19-IL2 immunocytokine in human melanoma xenografts

// Paola Orecchia 1,3 , Romana Conte 1 , Enrica Balza 2 , Gabriella Pietra 1,3 , Maria Cristina Mingari 1,3 and Barbara Carnemolla 1 1 Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy 2 Laboratory of Cell Biology, IRCCS AOU San Martino-IST, Genoa, Italy 3 Department of Experimental Medicine, University of Genoa, Genoa, Italy Correspondence to: Barbara Carnemolla, email: // Keywords : vasculogenic/vascular mimicry, angiogenesis, scFv OC-46F2 anti Syndecan-1, melanoma combined therapy, immunocytokine L19-IL2 Received : June 16, 2015 Accepted : September 23, 2015 Published : October 09, 2015 Abstract Anti-angiogenic therapy of solid tumors has until now failed to produce the long lasting clinical benefits desired, possibly due to the complexity of the neoangiogenic process. Indeed, a prominent role is played by “vasculogenic” or “vascular” mimicry (VM), a phenomenon in which aggressive cancer cells form an alternative microvascular circulation, independently of endothelial cell angiogenesis. In this study we observed, in melanoma patient cell lines having vasculogenic/stem-cell like phenotype and in melanoma tumors, the Syndecan-1 co-expression with VM markers, such as CD144 and VEGFR-2. We show that melanoma cells lose their ability to form tubule-like structures in vitro after blocking Syndecan-1 activity by the specific human recombinant antibody, OC-46F2. Moreover, in a human melanoma xenograft model, the combined therapy using OC-46F2 and L19-IL2, an immunocytokine specific for the tumor angiogenic-associated B-fibronectin isoform(B-FN), led to a complete inhibition of tumor growth until day 90 from tumor implantation in 71% of treated mice, with statistically significant differences compared to groups treated with OC-46F2 or L19-IL2 as monotherapy. Furthermore, in the tumors recovered from mice treated with OC-46F2 either as monotherapy or in combination with L19-IL2, we observed a dramatic decrease of vascular density and loss of VM structures. These findings indicate for the first time a role of Syndecan-1 in melanoma VM and that targeting Syndecan-1, together with B-FN, could be promising in improving the treatment of metastatic melanoma.