Macrophages facilitate resistance to anti-VEGF therapy by altered VEGFR expression

Heather J. Dalton, Sunila Pradeep, Michael McGuire, Yared Hailemichael, Shaolin Ma, Yasmin Lyons, Guillermo N. Armaiz-Pena, Rebecca A. Previs, Jean Marie Hansen, Rajesha Rupaimoole, Vianey Gonzalez-Villasana, Min Soon Cho, Sherry Y. Wu, Lingegowda S. Mangala, Nicholas B. Jennings, Wei Hu, Robert Langley, Hong Mu, Michael Andreeff, Menashe Bar-EliWillem Overwijk, Prahlad Ram, Gabriel Lopez-Berestein, Robert L. Coleman, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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 anti-angiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers.

Original languageEnglish (US)
Pages (from-to)7034-7046
Number of pages13
JournalClinical Cancer Research
Issue number22
StatePublished - Nov 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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