P08.36 TGF-β pathway-mediated escape from VEGF blockade is linked with angiogenesis and immune-suppression in murine glioma models

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The vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β are key target molecules in glioblastoma that are interdependently regulated. Both pathways drive key malignant features in glioma cells such as angiogenesis, invasiveness and immunosuppression. Here we explore whether TGF-β acts as an escape pathway from VEGF inhibition using gene expression profiling and in vitro and in vivo studies in a panel of syngeneic mouse glioma models. In vivo, single agent activity was observed for the VEGF antibody B20-4.1.1 in three (SMA-540, SMA-560 and GL-261), and for the TGF-β receptor I antagonist LY2157299 in two (SMA-540 and SMA-560) of four mouse glioma models. Transcriptomic profiling of the four mouse glioma models revealed that SMA-497 and GL-261, while unresponsive to LY2157299, were the most immunogenic tumors as defined by Gene Ontology; specifically, up-regulation of chemokine/chemoreceptors genes involved in immune cell recruitment and interferon-related genes were found. Co-targeting of VEGF and TGF-β was ineffective in one refractory model (SMA-497), in which no major changes in tumor immune-infiltrating cells were detected upon mono- or co-treatment settings. Significant prolongation of survival in the GL-261 model was associated with early stage increased infiltration of CD8+ cells, lower numbers of CD11b+ macrophages/microglia and sustained suppression of angiogenesis compared to anti-VEGF treatment alone. Phosphorylated SMAD2 was increased in both tumor cells and CD45+ leukocytes during anti-angiogenic treatment pointing to the possibility of a TGF-β-induced immunosuppressive micro-milieu that is efficiently counteracted by concomitant administration of LY2157299. In conclusion, our study highlights the biological heterogeneity of glioblastoma even among simple mouse models and illustrates that co-targeting of the VEGF and TGF-β pathways might lead to improved tumor control in subsets of glioblastoma linked with angiogenesis impairment and general reduction of the immune-suppressive phenotype. This study was supported by a grant from Oncosuisse (KFS-02694-08-2010)

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