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Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells

Abstract

Vascular endothelial growth factor (VEGF) is an essential regulator of normal and abnormal blood vessel growth. A monoclonal antibody (mAb) that targets VEGF suppresses tumor growth in murine cancer models and human patients. We investigated cellular and molecular events that mediate refractoriness of tumors to anti-angiogenic therapy. Inherent anti-VEGF refractoriness is associated with infiltration of the tumor tissue by CD11b+Gr1+ myeloid cells. Recruitment of these myeloid cells is also sufficient to confer refractoriness. Combining anti-VEGF treatment with a mAb that targets myeloid cells inhibits growth of refractory tumors more effectively than anti-VEGF alone. Gene expression analysis in CD11b+Gr1+ cells isolated from the bone marrow of mice bearing refractory tumors reveals higher expression of a distinct set of genes known to be implicated in active mobilization and recruitment of myeloid cells. These findings indicate that, in our models, refractoriness to anti-VEGF treatment is determined by the ability of tumors to prime and recruit CD11b+Gr1+ cells.

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Figure 1: Recruit of BMMNCs by tumor cell lines refractory to anti-VEGF treatment.
Figure 2: BMMNCs and tumor associated-GFP+ cells from mice bearing EL4 and LLC tumors contribute to refractoriness to anti-VEGF treatment.
Figure 3: CD11b+Gr1+ cells isolated from mice bearing refractory tumors are a major hematopoietic cell population mediating refractoriness to anti-VEGF treatment.
Figure 4: Effects of combining anti-VEGF with an anti-Gr1 on the growth of EL4 and LLC tumors.
Figure 5: Comparison of the efficacy of anti-VEGF-A mAb and mFlt(1-3)-IgG in refractory and sensitive tumors.
Figure 6: Distinct mechanisms mediate refractoriness to anti-VEGF and chemotherapeutic agents.
Figure 7: A distinct gene expression profile is associated with bone marrow CD11b+Gr1+ in mice bearing refractory tumors.

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Acknowledgements

We thank Leo DeGuzman and Jose Zavala-Solario for their help with animal experiments, Jim Cupp, Laurie Gilmour and Mike Hamilton for FACS advice and Josh Kaminker for help with the gene expression analysis.

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F.S., H.-P.G. and N.F. designed the experiments and wrote the manuscript. F.S. analyzed the data and performed experiments. F.S., X.W., A.K.M., C.Z., M.E.B. and S.S. performed experiments. G.F. provided reagents. H.-P.G. and N.F. are both senior authors.

Corresponding authors

Correspondence to Farbod Shojaei or Napoleone Ferrara.

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The authors are shareholders of Genetech, Inc.

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Shojaei, F., Wu, X., Malik, A. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25, 911–920 (2007). https://doi.org/10.1038/nbt1323

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  • DOI: https://doi.org/10.1038/nbt1323

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