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

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• VEGF-targeted therapies show limited efficacy in cancer due to common acquired resistance.
• Mechanisms driving resistance to anti-VEGF therapy are not fully understood.

Purpose of the Study:

• To investigate the role of immune cells, specifically macrophages, in the development of resistance to VEGF blockade.
• To characterize the mechanisms by which macrophages contribute to anti-VEGF therapy resistance.

Main Methods:

• Established preclinical models of adaptive resistance to anti-VEGF antibody (AVA) in murine cancer models.
• Conducted in vitro and in vivo studies to assess the impact of macrophages on AVA resistance.
• Utilized macrophage depletion and macrophage-deficient models to evaluate their role.

Main Results:

• Macrophages are recruited to the tumor microenvironment and are critical for the emergence of AVA resistance.
• Depletion of macrophages halted tumor growth and prolonged survival in resistant models.
• Macrophage-deficient mice failed to develop AVA resistance, which could be induced by macrophage injection.
• Downregulation of VEGFR-1/VEGFR-3 on macrophages correlated with activation of alternative angiogenic pathways.

Conclusions:

• Macrophages play a previously unrecognized role in mediating resistance to anti-VEGF therapy.
• Findings offer new insights into the limited efficacy of antiangiogenesis treatments.
• Identified macrophages as a potential therapeutic target for combination strategies in ovarian and other cancers.