Di Tacchio, Mariangela, Macas, Jadranka, Weissenberger, Jakob, Sommer, Kathleen, Baehr, Oliver, Steinbach, Joachim P., Senft, Christian, Seifert, Volker, Glas, Martin, Herrlinger, Ulrich, Krex, Dietmar, Meinhardt, Matthias, Weyerbrock, Astrid ORCID: 0000-0001-9060-4462, Timmer, Marco, Goldbrunner, Roland, Deckert, Martina, Scheel, Andreas H., Buettner, Reinhard, Grauer, Oliver M., Schittenhelm, Jens, Tabatabai, Ghazaleh ORCID: 0000-0002-3542-8782, Harter, Patrick N., Guenther, Stefan, Devraj, Kavi, Plate, Karl H. and Reiss, Yvonne (2019). Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF. Cancer Immunol. Res., 7 (12). S. 1910 - 1928. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2326-6074

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Di Tacchio, MariangelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Macas, JadrankaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weissenberger, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommer, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baehr, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinbach, Joachim P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Senft, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seifert, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glas, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrlinger, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krex, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meinhardt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weyerbrock, AstridUNSPECIFIEDorcid.org/0000-0001-9060-4462UNSPECIFIED
Timmer, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grauer, Oliver M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schittenhelm, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tabatabai, GhazalehUNSPECIFIEDorcid.org/0000-0002-3542-8782UNSPECIFIED
Harter, Patrick N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devraj, KaviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plate, Karl H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiss, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-125829
DOI: 10.1158/2326-6066.CIR-18-0865
Journal or Publication Title: Cancer Immunol. Res.
Volume: 7
Number: 12
Page Range: S. 1910 - 1928
Date: 2019
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2326-6074
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BLOOD-BRAIN-BARRIER; IN-VIVO; EXPRESSION; ANGIOGENESIS; TIE2; TEMOZOLOMIDE; VASCULATURE; MACROPHAGES; STABILIZES; BLOCKADEMultiple languages
Oncology; ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12582

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