Targeted disruption of lectin-glycan lattices abrogates hypoxia-driven angiogenesis, restores immune function and promotes remodeling of tumor vascular networks

CROCI DO; SALATINO M; OUYANG J; MASCANFRONI I; CERLIANI JP; DERGAN-DYLON S; ILARREGUI JM; TOSCANO MA; SUNDBLAD, V; SHIPP M; RABINOVICH GA

Congreso; Raunion Anual de la FAIC; 2010

Resistance to VEGF-targeted antiangiogenic therapies suggests the contribution of alternative pathways to hypoxia-driven neovascularization. Previously we showed that galectin-1 (Gal1)-glycan lattices couple tumor hypoxia to VEGFR2-mediated angiogenesis through mechanism that are independent of HIF-1a and VEGF. The present study was conducted to elucidate whether disruption of Gal1-glycan lattices, using an anti-Gal1 mAb with blocking activity, may contribute to simultaneously remodeling of tumor vascular networks and stimulation of anti-tumor T-cell responses. In a xenograft model of human Kaposi´s sarcoma as well as in syngeneic B16 mouse melanoma, disruption of Gal1-glycan lattices abrogated hypoxia-driven angiogenesis, as shown by reduced frequency of CD34+ endothelial cells (ECs) (3-fold; p<0.01), increased association of ECs with mature pericytes (aSMA+, desmin+ and RGS5-) (2-fold; p<0.01) and decreased vessel diameter (1.5 fold; p<0.01) in tumors treated with anti Gal1mAb (F8.G7) versus those treated with isotype control. Administration of the F8.G7 mAb in the B16 model promoted a significant reduction in tumor growth (3.5-fold 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 compared to mice receiving control isotope mAb. 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. This therapeutic approach was compared to shRNA strategies revealing comparable clinical outcomes. In human biopsies (n=15 KS and n=24 melanoma) expression of Gal-1 and specific glycans delineated the transition toward a malignant pro-angiogenic phenotype. Thus, disruption of lectin-glycan lattices, not only evokes an unleashed anti tumor immune response, but also reduces angiogenesis and favors remodeling of tumor vascular networks.