Date of Graduation
Masters of Science (MS)
Anil K. Sood
Background: The clinical implementation of therapies targeting the VEGF pathway in cancer has been limited by acquired resistance; yet, the mechanisms by which this occurs is unclear. We investigated the role of macrophages in the development of acquired resistance to anti-VEGF antibody (AVA) therapy.
Materials and Methods: We first established a murine ovarian cancer model of resistance to anti-VEGF therapy. Using this model we investigated changes in macrophage infiltration during AVA sensitive and resistant phases. We also investigated the in vivo effects of macrophage depletion at the emergence of anti-VEGF resistance and in upfront combination with AVA therapy. In vitro, we assessed differences in viability and invasion/migration in AVA sensitive and resistant macrophages. We also investigated macrophage VEGF receptor expression in response to AVA therapy. Finally, we performed high throughput analyses to determine pathways important in modulating macrophage response to AVA.
Results: We show that macrophages are actively recruited to the tumor microenvironment, where their accumulation correlates with the emergence of anti-VEGF resistance. Importantly, depletion of macrophages at the emergence of anti-VEGF resistance halts tumor growth and significantly prolongs survival in murine models. Additionally, the upfront combination of anti-VEGF therapy with macrophage depletion is synergistic, decreasing tumor growth in vivo. We found downregulation of macrophage VEGFR-1 expression in conjunction with upregulation of alternative angiogenic and anti-apoptotic pathways at the emergence of resistance, possibly facilitating escape from VEGF-directed therapies.
Conclusions: After establishing murine ovarian cancer models of anti-VEGF resistance, we demonstrate a previously unrecognized role for macrophages in adaptive resistance to anti-VEGF therapy. Depletion of macrophages restores sensitivity to AVA therapy and reduces tumor growth in combination with VEGF blockade. Collectively, this study highlights macrophages as catalysts in the development of anti-VEGF resistance and offers strategies to modulate the influence of macrophages, thus improving the effectiveness of anti-VEGF therapy.
Macrophages, Adaptive Resistance, Anti-VEGF therapy