CONICET | Buscador de Institutos y Recursos Humanos

Targeting glycosylation-dependent circuits inhibits non-canonical VEGFR2 activation and promotes vascular remodeling and immunity DO. Croci1, ID. Mascanfroni1, JP. Cerliani1, M. Salatino1 , T. D´Alotto, JM. Ilarregui1, V. Sundblad1, MA. Toscano1, S. Dergan-Dylon1, J. Ouyan, MA. Shipp2 and GA. Rabinovich1. 1.Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires, Argentina. 2. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, United States; Resistance to antiangiogenic therapies suggests the contribution of non-canonical pathways to hypoxia-driven neovascularization. The aim of this study was to evaluate whether Galectin1 (Gal1)-glycan interactions link tumor hypoxia to neovascularization and to investigate whether disruption of these lattices using an anti Gal1 mAb, may contribute to remodeling tumor vascular networks and stimulation of anti-tumor immune responses. We first examined the glycosylation of endothelilal cells (ECs) in diferent microenvironments. In contrast to ECs stimulated with pro-inflammatory stimuli, ECs exposed to tolerogenic, proliferative or hypoxic microenvironment exhibited a substantial up-regulation of cell surface glycans that are critical for Gal-1 binding (p<0.01). In this regard we found a 2-fold increase phosphorylation of VEGFR2 signaling pathway upon exposure of ECs to Gal1. Furthermore Co-Ip experiments revealed specific association of Gal1 with VEGFR2 through N-glycan-dependent interactions. Consistently, VEGFR2 blockade prevented Gal1-induced ECs migration (p<0.01) and morphogenesis (p<0.05), whereas blockade of VEGFR1, VEGFR3, or VEGF had no effect. In vivo disruption of Gal1-glycan lattices, using a anti Gal1 mAb ( F8.G7), promotes the remodeling of tumor vasculature by increased association of ECs with mature pericytes (p<0.01) and decreased vessel diameter (p<0.01) in tumors. Administration of the F8.G7 mAb in the B16, LLC1 or EL4 models promoted a significant reduction in tumor growth (p<0.01) and evoked a T-cell specific immune response, as shown by increased T-cell proliferation (p<0.01) and augmented IFN-g (p<0.05) and IL-17 (p<0.05) production. Moreover, tumor-draining LN of F8.G7-treated mice had lower frequency of CD4+CD25+Foxp3+ regulatory T cells (p<0.05) and lower IL-10 secretion (p<0.05) than mice receiving isotype control. Our findings highlight the versatility of endogenous lectins and the dynamics of the ?glycome? during cancer progression and provide the first evidence of a multitargeted agent capable of promoting vascular remodeling and overcoming tumor immunosuppression through specific interruption of lectin-glycan interactions.

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