TY - JOUR
T1 - Macrophages facilitate resistance to anti-VEGF therapy by altered VEGFR expression
AU - Dalton, Heather J.
AU - Pradeep, Sunila
AU - McGuire, Michael
AU - Hailemichael, Yared
AU - Ma, Shaolin
AU - Lyons, Yasmin
AU - Armaiz-Pena, Guillermo N.
AU - Previs, Rebecca A.
AU - Hansen, Jean Marie
AU - Rupaimoole, Rajesha
AU - Gonzalez-Villasana, Vianey
AU - Cho, Min Soon
AU - Wu, Sherry Y.
AU - Mangala, Lingegowda S.
AU - Jennings, Nicholas B.
AU - Hu, Wei
AU - Langley, Robert
AU - Mu, Hong
AU - Andreeff, Michael
AU - Bar-Eli, Menashe
AU - Overwijk, Willem
AU - Ram, Prahlad
AU - Lopez-Berestein, Gabriel
AU - Coleman, Robert L.
AU - Sood, Anil K.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-17-0647
DO - 10.1158/1078-0432.CCR-17-0647
M3 - Article
C2 - 28855350
AN - SCOPUS:85034821972
SN - 1078-0432
VL - 23
SP - 7034
EP - 7046
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -