Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells.
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.
Shojaei
Farbod
F
Genentech, Inc., 1 DNA Way, S. San Francisco, California 94080, USA. farbod@gene.com
Wu
Xiumin
X
Malik
Ajay K
AK
Zhong
Cuiling
C
Baldwin
Megan E
ME
Schanz
Stefanie
S
Fuh
Germaine
G
Gerber
Hans-Peter
HP
Ferrara
Napoleone
N
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D039481:CD11b Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse