TY  - JOUR
AU  - Di Tacchio, Mariangela
AU  - Macas, Jadranka
AU  - Weissenberger, Jakob
AU  - Sommer, Kathleen
AU  - Bähr, Oliver
AU  - Steinbach, Joachim P
AU  - Senft, Christian
AU  - Seifert, Volker
AU  - Glas, Martin
AU  - Herrlinger, Ulrich
AU  - Krex, Dietmar
AU  - Meinhardt, Matthias
AU  - Weyerbrock, Astrid
AU  - Timmer, Marco
AU  - Goldbrunner, Roland
AU  - Deckert, Martina
AU  - Scheel, Andreas H
AU  - Büttner, Reinhard
AU  - Grauer, Oliver M
AU  - Schittenhelm, Jens
AU  - Tabatabai, Ghazaleh
AU  - Harter, Patrick
AU  - Günther, Stefan
AU  - Devraj, Kavi
AU  - Plate, Karl H
AU  - Reiss, Yvonne
TI  - Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF.
JO  - Cancer immunology research
VL  - 7
IS  - 12
SN  - 2326-6074
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2020-00057
SP  - 1910 - 1927
PY  - 2019
AB  - Glioblastoma (GBM) is a non-T-cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.
LB  - PUB:(DE-HGF)16
C6  - pmid:31597643
DO  - DOI:10.1158/2326-6066.CIR-18-0865
UR  - https://inrepo02.dkfz.de/record/148865
ER  -