Kashyap, Abhishek SAbhishek SKashyapSchmittnaegel, MartinaMartinaSchmittnaegelRigamonti, NicolòNicolòRigamontiPais-Ferreira, DanielaDanielaPais-FerreiraMueller, PhilippPhilippMuellerBuchi, MelanieMelanieBuchiOoi, Chia-HueyChia-HueyOoiKreuzaler, MatthiasMatthiasKreuzalerHirschmann, PetraPetraHirschmannGuichard, AlanAlanGuichardRieder, NataschaNataschaRiederBill, RubenRubenBillHerting, FrankFrankHertingKienast, YvonneYvonneKienastDirnhofer, StefanStefanDirnhoferKlein, ChristianChristianKleinHoves, SabineSabineHovesRies, Carola HCarola HRiesCorse, EmilyEmilyCorseDe Palma, MicheleMicheleDe PalmaZippelius, AlfredAlfredZippelius2024-09-022024-09-022020-01-07https://boris-portal.unibe.ch/handle/20.500.12422/37193Cancer 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.enCD40 VEGFA angiogenesis angiopoetin immunotherapy600 - Technology::610 - Medicine & healtharticle10.7892/boris.1466783188900410.1073/pnas.1902145116