Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-01, Vol.117 (1), p.541-551
• Main Authors: 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, Zippelius, Alfred
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Angiopoietin; Angiopoietin-2 - antagonists & inhibitors; Angiopoietin-2 - metabolism; Animals; Antiangiogenics; Antibodies; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological Sciences; Blood vessels; Cancer; Cancer immunotherapy; CD40 antigen; CD40 Antigens - agonists; CD40 Antigens - immunology; CD8 antigen; Cell activation; Cell Line, Tumor - transplantation; Cytotoxicity; Dendritic cells; Disease Models, Animal; Drug Synergism; Effector cells; Female; Growth factors; Humans; Immunotherapy; Inflammation; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Macrophages; Metastases; Mice; Microvasculature; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; PNAS Plus; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1902145116

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 tumormicroenvironment, 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.