Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.

Published

Journal Article

Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood.Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance.Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy.Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034-46. ©2017 AACR.

Full Text

Duke Authors

Cited Authors

  • Dalton, HJ; Pradeep, S; McGuire, M; Hailemichael, Y; Ma, S; Lyons, Y; Armaiz-Pena, GN; Previs, RA; Hansen, JM; Rupaimoole, R; Gonzalez-Villasana, V; Cho, MS; Wu, SY; Mangala, LS; Jennings, NB; Hu, W; Langley, R; Mu, H; Andreeff, M; Bar-Eli, M; Overwijk, W; Ram, P; Lopez-Berestein, G; Coleman, RL; Sood, AK

Published Date

  • November 15, 2017

Published In

Volume / Issue

  • 23 / 22

Start / End Page

  • 7034 - 7046

PubMed ID

  • 28855350

Pubmed Central ID

  • 28855350

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-17-0647

Language

  • eng

Conference Location

  • United States