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

CROCI DO; SALATINO M; JING O; MASCANFRONI ID; CERLIANI JP; DERGAN DYLON SL; ILARREGUI JM; TOSCANO MA; SUNDBLAD V; PESOA S; SHIPP M; RABINOVICH GA

Congreso; First French-Argentine Immunology Congress; 2010

Sociedad Argentina de Inmunología

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- 1alpha and VEGF. The present study was conducted to elucidatewhether 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 antitumorT-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 (2.7 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 (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 IFNg (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.