Kashyap, Abhishek S.Schmittnaegel, MartinaRigamonti, NicolòPais-Ferreira, DanielaMueller, PhilippBuchi, MelanieOoi, Chia-HueyKreuzaler, MatthiasHirschmann, PetraGuichard, AlanRieder, NataschaBill, RubenHerting, FrankKienast, YvonneDirnhofer, StefanKlein, ChristianHoves, SabineRies, Carola H.Corse, EmilyDe Palma, MicheleZippelius, Alfred2020-02-142020-02-142020-02-142020-01-0710.1073/pnas.1902145116https://infoscience.epfl.ch/handle/20.500.14299/165559Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.text::journal::journal article::research article