Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Schiffmann, Lars Mortimer UNSPECIFIED UNSPECIFIED UNSPECIFIED Fritsch, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebauer, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Guenther, Saskia Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Stair, Neil Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger, Jens Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Thangarajah, Fabinshy UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieplinger, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Bludau, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, Hakan UNSPECIFIED UNSPECIFIED UNSPECIFIED Gobel, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Zander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hilberg, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane Josephine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED Coutelle, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language VASCULAR NORMALIZATION; RESISTANCE; GROWTH; CELLS; ANGIOPOIETIN-2; BEVACIZUMAB; INHIBITION; TARGET Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15943