Schiffmann, Lars Mortimer, Fritsch, Melanie, Gebauer, Florian, Guenther, Saskia Diana, Stair, Neil Richard, Seeger, Jens Michael, Thangarajah, Fabinshy, Dieplinger, Georg, Bludau, Marc, Alakus, Hakan, Gobel, Heike, Quaas, Alexander, Zander, Thomas, Hilberg, Frank, Bruns, Christiane Josephine, Kashkar, Hamid and Coutelle, Oliver (2019). Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br. J. Cancer, 120 (1). S. 69 - 79. LONDON: NATURE PUBLISHING GROUP. ISSN 1532-1827

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Abstract

BACKGROUND: Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. METHODS: A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. RESULTS: The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177- metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. CONCLUSIONS: Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schiffmann, Lars MortimerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritsch, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gebauer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, Saskia DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stair, Neil RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, Jens MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thangarajah, FabinshyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieplinger, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bludau, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alakus, HakanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gobel, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quaas, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilberg, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruns, Christiane JosephineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coutelle, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-159439
DOI: 10.1038/s41416-018-0198-3
Journal or Publication Title: Br. J. Cancer
Volume: 120
Number: 1
Page Range: S. 69 - 79
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1532-1827
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
VASCULAR NORMALIZATION; RESISTANCE; GROWTH; CELLS; ANGIOPOIETIN-2; BEVACIZUMAB; INHIBITION; TARGETMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15943

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