Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.
Angiogenesis Inhibitors
/ pharmacology
Angiopoietin-2
/ antagonists & inhibitors
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
CD40 Antigens
/ agonists
Cell Line, Tumor
/ transplantation
Disease Models, Animal
Drug Synergism
Female
Humans
Lymphocytes, Tumor-Infiltrating
/ drug effects
Mice
Neoplasms
/ blood supply
Neovascularization, Pathologic
/ drug therapy
T-Lymphocytes, Cytotoxic
/ drug effects
Tumor Microenvironment
/ drug effects
Vascular Endothelial Growth Factor A
/ antagonists & inhibitors
CD40
VEGFA
angiogenesis
angiopoetin
immunotherapy
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
07 01 2020
07 01 2020
Historique:
pubmed:
1
1
2020
medline:
6
5
2020
entrez:
1
1
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31889004
pii: 1902145116
doi: 10.1073/pnas.1902145116
pmc: PMC6955310
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Angiopoietin-2
0
Angpt2 protein, mouse
0
Antineoplastic Agents, Immunological
0
CD40 Antigens
0
Vascular Endothelial Growth Factor A
0
vascular endothelial growth factor A, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
541-551Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: M.S., C.-H.O., N. Rieder, F.H., Y.K., C.K., S.H., C.H.R., and E.C. are former or current Roche employees. C.-H.O., N. Rieder, F.H., C.K., S.H., and C.H.R. are Roche stock holders. M.D.P. and A.Z. received research funding from Roche. The other authors declare that they have no competing interests.
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