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

• Published in: Nature biotechnology Vol. 25; no. 8; pp. 911 - 920
• Main Authors: Shojaei, Farbod, Ferrara, Napoleone, Wu, Xiumin, Malik, Ajay K, Zhong, Cuiling, Baldwin, Megan E, Schanz, Stefanie, Fuh, Germaine, Gerber, Hans-Peter
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.08.2007
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Biological and medical sciences; Biotechnology; Bone marrow; Cancer; CD11b Antigen - metabolism; Cell Line, Tumor; Cellular biology; Drug Resistance, Neoplasm; Fundamental and applied biological sciences. Psychology; Gene expression; Health. Pharmaceutical industry; Immunotherapy; Industrial applications and implications. Economical aspects; Infiltration; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Pharmacology. Drug treatments; Receptors, Chemokine - metabolism; Rodents; Treatment Outcome; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Antineoplastic agent; Human; Animal model; Therapy; Targeting; Rodentia; Monoclonal antibody; Malignant tumor; Gene expression; Myeloid cell; Resistance; Vertebrata; Mammalia; Vascular endothelium growth factor; Treatment; Mouse; Antiangiogenic agent; Cancer
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1323

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.