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

[img]
Preview
Text
pnas.201902145.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND).

Download (2MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Bill, Ruben

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

25 Sep 2020 09:42

Last Modified:

25 Sep 2020 09:42

Publisher DOI:

10.1073/pnas.1902145116

PubMed ID:

31889004

Uncontrolled Keywords:

CD40 VEGFA angiogenesis angiopoetin immunotherapy

BORIS DOI:

10.7892/boris.146678

URI:

https://boris.unibe.ch/id/eprint/146678

Actions (login required)

Edit item Edit item
Provide Feedback