학술논문
Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.
Document Type
Article
Author
Kashyap, Abhishek S.; Schmittnaegel, Martina; Rigamonti, Nicolò; Pais-Ferreira, Daniela; Mueller, Philipp; Buchi, Melanie; Chia-Huey Ooi; Kreuzaler, Matthias; Hirschmann, Petra; Guichard, Alan; Rieder, Natascha; Bil, Ruben; Herting, Frank; Kienast, Yvonne; Dirnhofer, Stefan; Klein, Christian; Hoves, Sabine; Ries, Carola H.; Corse, Emily; De Palma, Michele
Source
Subject
*VASCULAR endothelial growth factors
*TUMOR microenvironment
*CYTOTOXIC T cells
*IMMUNOTHERAPY
*CELL tumors
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Language
ISSN
0027-8424
Abstract
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. [ABSTRACT FROM AUTHOR]