Research Project 3 Galectin-1-glycan interactions: Novel regulatory checkpoints linking immunosuppression and angiogenesis in virally induced cancers

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Project 3 Abstract Viral oncogenesis is responsible of 20% of total cancer. In particular, KSHV and HPV are the most common oncogenic viruses infecting millions of patients per year. Although the efficiency of these viruses to alter cell cycle regulation and manipulate cell signal pathways they need a co-cofactor to develop neoplastic lesions. Frequently, HIV co-infection is the most important association with KSHV and HPV because attenuates immune response. Active antiretroviral treatment (HAART) has become an effective therapy but at time patients progress and require additional treatments . Galectin-1 (Gal1), a glycan binding protein with immunosuppressive effects modulates tumor microenvironments by inducing apoptosis of activated T cells, promoting IL-27- Foxp3+ Tregs. Recently, we have tolerogenic dendritic cells and expanding demonstrated that Gal1-N-glycans on VEGFR2 links tumor hypoxia to aberrant angiogenesis and preserves vascularization in anti-VEGF refractory tumors facilitating tumor growth and metastasis. These data, suggest that targeting Gal1-N-glycan interactions may overcome resistance to anti-cancer therapies by promoting compensatory angiogenesis and by potentiating immune responses. Specific changes in the glycome and up-regulation of Gal1 in infected viral oncogenic-cells seems to be the key for the development of a new generation of therapies for sarcoma kaposi tumors and HPV-associated malignancies. Anti-Gal1 mAbs could re-educate immune system improving actual therapies. In this project, we propose to use an interdisciplinary approach to explore the Gal1-N-glycan axis as a potential player in pathogenesis of viral-associated tumors by fine tuning critical signaling pathways and promoting oncogenic inflammation with the ultimate goal to improve a new generation diagnostic and therapeutic strategies aimed at limiting tumor growth by suppressing PDGFRA-dependent aberrant signaling and potentiating antitumor immunity.