title: Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy.
abstract: Antiangiogenic therapy is commonly used in the clinic, but its beneficial effects are short-lived, leading to tumor relapse within months. Here, we found that the efficacy of angiogenic inhibitors targeting the VEGF/VEGFR pathway was dependent on induction of the angiostatic and immune-stimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune suppression by activating PI3K signaling in all CD11b+ cells, rendering tumors nonresponsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade because tumor-associated macrophages (TAMs) would compensate for the lack of such cells and vice versa, leading to an oscillating pattern of distinct immune-cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which antiangiogenic therapy remained efficient.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Rivera
authors.affiliation: Université Lyon 1, Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon, Bron Cedex 69677, France.
authors.forename: David
authors.initials: D
authors.lastname: Meyronet
authors.affiliation: Université Lyon 1, Service d'Anatomie Pathologique, Hôpital Édouard Herriot, Hospices Civils de Lyon, Lyon Cedex 69003, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Department of Head and Neck Surgery, Research Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
authors.affiliation: Department of Medicine, UCSF Mount Zion Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bergsland
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: gabriele.bergers@ucsf.edu.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Bergers
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D042361:Mammary Glands, Human / Q000098:blood supply; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D040262:Receptors, Vascular Endothelial Growth Factor