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000148865 1001_ $$0P:(DE-HGF)0$$aDi Tacchio, Mariangela$$b0
000148865 245__ $$aTumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF.
000148865 260__ $$aPhiladelphia, Pa.$$bAACR$$c2019
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000148865 520__ $$aGlioblastoma (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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000148865 7001_ $$00000-0002-1661-2525$$aMacas, Jadranka$$b1
000148865 7001_ $$aWeissenberger, Jakob$$b2
000148865 7001_ $$aSommer, Kathleen$$b3
000148865 7001_ $$0P:(DE-HGF)0$$aBähr, Oliver$$b4
000148865 7001_ $$0P:(DE-HGF)0$$aSteinbach, Joachim P$$b5
000148865 7001_ $$0P:(DE-HGF)0$$aSenft, Christian$$b6
000148865 7001_ $$0P:(DE-HGF)0$$aSeifert, Volker$$b7
000148865 7001_ $$0P:(DE-He78)a44ef83e4213638f939d4e35a3c52d34$$aGlas, Martin$$b8
000148865 7001_ $$aHerrlinger, Ulrich$$b9
000148865 7001_ $$0P:(DE-HGF)0$$aKrex, Dietmar$$b10
000148865 7001_ $$aMeinhardt, Matthias$$b11
000148865 7001_ $$aWeyerbrock, Astrid$$b12
000148865 7001_ $$aTimmer, Marco$$b13
000148865 7001_ $$aGoldbrunner, Roland$$b14
000148865 7001_ $$aDeckert, Martina$$b15
000148865 7001_ $$aScheel, Andreas H$$b16
000148865 7001_ $$aBüttner, Reinhard$$b17
000148865 7001_ $$aGrauer, Oliver M$$b18
000148865 7001_ $$00000-0002-9168-6209$$aSchittenhelm, Jens$$b19
000148865 7001_ $$0P:(DE-HGF)0$$aTabatabai, Ghazaleh$$b20
000148865 7001_ $$0P:(DE-He78)b15b56a6ed37417d476470c60c0140ff$$aHarter, Patrick$$b21
000148865 7001_ $$aGünther, Stefan$$b22
000148865 7001_ $$00000-0002-5005-3413$$aDevraj, Kavi$$b23
000148865 7001_ $$0P:(DE-HGF)0$$aPlate, Karl H$$b24
000148865 7001_ $$0P:(DE-HGF)0$$aReiss, Yvonne$$b25
000148865 773__ $$0PERI:(DE-600)2732517-9$$a10.1158/2326-6066.CIR-18-0865$$gVol. 7, no. 12, p. 1910 - 1927$$n12$$p1910 - 1927$$tCancer immunology research$$v7$$x2326-6074$$y2019
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