Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.

Kashyap, Abhishek S; Schmittnaegel, Martina; Rigamonti, Nicolò; Pais-Ferreira, Daniela; Mueller, Philipp; Buchi, Melanie; Ooi, Chia-Huey; Kreuzaler, Matthias; Hirschmann, Petra; Guichard, Alan; Rieder, Natascha; Bill, Ruben; Herting, Frank; Kienast, Yvonne; Dirnhofer, Stefan; Klein, Christian; Hoves, Sabine; Ries, Carola H; Corse, Emily; De Palma, Michele; ... (2020). Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 117(1), pp. 541-551. National Academy of Sciences NAS 10.1073/pnas.1902145116

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Cancer 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.

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