Abstract 2982: Macrophages modulate adaptive resistance to anti-angiogenic therapy

Abstract

Abstract Targeted anti-angiogenic therapies were a highly anticipated addition to cancer treatment, but their clinical use has been tempered by the development of resistance. To understand the role of immune cells in potentially mediating such resistance, we carried out systematic immune cell profiling in a syngeneic ovarian cancer mouse model following treatment with the B20 anti-VEGF antibody. Following injection of luciferase-labeled cancer cells and initiation of treatment, mice (n=8/group) were divided into B20-sensitive and resistant groups based on longitudinal bioluminescence imaging of tumor burden. Immune cell profiling confirmed a dramatic increase in macrophages with emergence of resistance to B20. Using the syngeneic model, resistance to B20 was documented with bioluminescence imaging as an increase in tumor burden in mice with previously stable disease. Zoledronic acid, a macrophage-depleting bisphosphonate, was then added to B20 treatment. Restoration of sensitivity to B20 with the addition of zoledronic acid was demonstrated by a 68% prolongation of survival in this treatment group as compared to those receiving B20 alone (p<0.0001). Zoledronic acid in combination with the VEGF antibody, bevacizumab, significantly reduced both tumor size and nodules when compared to either drug alone in additional orthotopic models of ovarian cancer. CD68 staining confirmed significantly reduced macrophage numbers in tumor samples following treatment with zoledronic acid. In vitro immunofluorescence imaging of macrophages following prolonged exposure to anti-VEGF therapy showed downregulation of VEGF receptors compared to short-term exposure, suggesting a possible mechanism for their persistence in an anti-VEGF resistant microenvironment. Collectively, these data demonstrate a novel role for macrophages in resistance to anti-VEGF therapy and offer a new therapeutic strategy to overcome this problem with important translational implications. Citation Format: Heather J. Dalton, Sunila Pradeep, Guillermo N. Armaiz-Pena, Rebecca Previs, Ashley Davis, Rajesha Rupaimoole, Behrouz Zand, Yared Hailemichael, Willem W. Overwijk, Gabriel Lopez-Berestein, Anil K. Sood. Macrophages modulate adaptive resistance to anti-angiogenic therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2982. doi:10.1158/1538-7445.AM2014-2982