23266066cir180865-sup-213312_3_supp_5691075_pvrg54.avi (2.38 MB)

Movie 3 from Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF

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posted on 2023-04-04, 00:46 authored by Mariangela Di Tacchio, Jadranka Macas, Jakob Weissenberger, Kathleen Sommer, Oliver Bähr, Joachim P. Steinbach, Christian Senft, Volker Seifert, Martin Glas, Ulrich Herrlinger, Dietmar Krex, Matthias Meinhardt, Astrid Weyerbrock, Marco Timmer, Roland Goldbrunner, Martina Deckert, Andreas H. Scheel, Reinhard Büttner, Oliver M. Grauer, Jens Schittenhelm, Ghazaleh Tabatabai, Patrick N. Harter, Stefan Günther, Kavi Devraj, Karl H. Plate, Yvonne Reiss

Aflibercept/AMG386 therapy renders a normalize vasculature with improved pericyte coverage (CollagenIV, red; desmin, green)

Funding

Clinical Translation Program

German Research Council

History

ARTICLE 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.

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Keywords

Cns Cancers Gliomas, Glioblastomas Immunotherapy Antibody immunotherapy Progression, Invasion & Metastasis Inflammation and tumor development Tumor Microenvironment Host-tumor interactions

Licence

CC BY