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

Abstract

BackgroundImmune 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.MethodsA 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.ResultsThe 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.ConclusionsOur 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.

Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial

“…It may be that other proangiogenic factors or tumor microenvironment proteins may have contributed to bevacizumab resistance. It was recently reported that tumor-infiltrating neutrophils may confer resistance to bevacizumab (49). Therefore, it may be valuable to expand the type of biomarkers measured.…”

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

“…As far as TANs are concerned, it was shown that they exert an anti-VEGF function. Specifically, Seeger et al showed that the presence of CD177 + neutrophils in colorectal cancer patients is associated with poor prognosis [93]. Finally, blocking of the Ang2/Tie axis was shown to reduce the tumor-promoting functions and recruitment of TAMs [92,94], and could be used as credentials denoting that blocking of secondary angiogenic mechanisms could improve anti-VEGF treatment [93].…”

Long non‑coding RNA CCAT1 promotes colorectal cancer cell migration, invasiveness and viability by upregulating VEGF via negative modulation of microRNA‑218

“…VEGF, a potent angiogenic factor, serves a key role in the formation of new blood vessels in CRC (41). VEGF is upregulated in CRC tissues and anti-VEGF therapy has been applied to patients with metastatic CRC (42,43). A previous study demonstrated that CCAT1 downregulation decreased thyroid cancer cell viability, proliferation, migration and invasion, and reduced VEGF expression (44).…”