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Br J Cancer. 2019 Jan;120(1):69-78. doi: 10.1038/s41416-018-0198-3. Epub 2018 Oct 31.

Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer.

Author information

1
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany. lars.schiffmann@uk-koeln.de.
2
Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. lars.schiffmann@uk-koeln.de.
3
Center for Integrated Oncology (CIO) Cologne Bonn, Gastrointestinal Cancer Group Cologne (GCGC), Kerpener Str. 62, 50924, Cologne, Germany. lars.schiffmann@uk-koeln.de.
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC) and Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
5
Department of General, Visceral and Cancer Surgery, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
6
Center for Integrated Oncology (CIO) Cologne Bonn, Gastrointestinal Cancer Group Cologne (GCGC), Kerpener Str. 62, 50924, Cologne, Germany.
7
Department of Gynaecology and Obstetrics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
8
Institute for Pathology, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
9
Department I of Internal Medicine, University of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.
10
Boehringer Ingelheim RCV, Doktor-Boehringer-Gasse 5-11, 1120, Vienna, Austria.

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.

PMID:
30377339
DOI:
10.1038/s41416-018-0198-3

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