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

• Published in: British journal of cancer Vol. 120; no. 1; pp. 69 - 78
• Main Authors: Schiffmann, Lars Mortimer, Fritsch, Melanie, Gebauer, Florian, Günther, Saskia Diana, Stair, Neil Richard, Seeger, Jens Michael, Thangarajah, Fabinshy, Dieplinger, Georg, Bludau, Marc, Alakus, Hakan, Göbel, Heike, Quaas, Alexander, Zander, Thomas, Hilberg, Frank, Bruns, Christiane Josephine, Kashkar, Hamid, Coutelle, Oliver
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2019; Nature Publishing Group
• Subjects: 692/4028/67/1504/1885; 692/4028/67/2328; 692/53/2423; Aged; Angiogenesis; Angiogenesis Inhibitors - administration & dosage; Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Bevacizumab; Bevacizumab - administration & dosage; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Depletion; Drug Resistance; Drug Resistance, Neoplasm - genetics; Epidemiology; Female; GPI-Linked Proteins - genetics; Humans; Hypoxia; Immunohistochemistry; Inhibition; Isoantigens - genetics; Leukocytes (neutrophilic); Male; Metastases; Metastasis; Mice; Middle Aged; Molecular Medicine; Monoclonal antibodies; Neoplasm Metastasis; Neoplastic Stem Cells - drug effects; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Neutrophils; Neutrophils - drug effects; Oncology; Patients; Receptors, Cell Surface - genetics; Targeted cancer therapy; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vesicular Transport Proteins - genetics; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-018-0198-3

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.