Non-classical monocytes contribute to treatment resistance against anti-VEGF cancer therapies
Although anti-VEGF therapies are commonly used to treat macular degeneration, these angiogenesis inhibitors have also been approved to target tumor growth and metastasis in several cancers. Because tumors depend on access to circulating blood to grow and metastasize, preventing angiogenesis may limit cancer progression. The success of anti-VEGF therapies in cancer has been limited, however, due to the ability of tumors to rapidly develop treatment resistance.
This week in the JCI, a study led by Dai Fukumura at Harvard Medical School and Massachusetts General Hospital has determined that immunosuppressive effects of non-classical Ly6Clo monocytes contribute to resistance against anti-VEGF therapies in mouse models of colorectal cancer. Researchers observed that treating colorectal tumors with VEGF inhibitors led to elevated expression of the chemokine CX3CL1. Elevations in CX3CL1 levels enhanced the recruitment of Ly6Clo monocytes into tumors, which in turn increased neutrophil migration and immunosuppressive IL-10 production within the tumor. Preventing Ly6Clo monocyte infiltration or blocking the receptor for CX3CL1 on monocytes improved the outcome of anti-VEGF therapies in the murine models. Together, these findings reveal a previously undescribed immunosuppressive function for Ly6Clo monocytes that plays a critical role in the development of treatment resistance to anti-VEGF therapies.
In the highlighted video: Jung et al. used real-time in vivo imaging to determine that CX3CL1/CX3CR1 signaling is required for Ly6Clo monocyte recruitment into tumors. The video visualizes Ly6Clo CX3CR1-expressing monocytes (green) flowing, rolling, and crawling through a blood vessel (red) as they infiltrate tumors. A rolling monocyte is observed beginning in the lower left corner, while a flowing monocyte is seen quickly moving through the upper left quadrant of the image.
Related articles
Abstract
Current anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6Clo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6Clo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6Clo monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clo monocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6Clo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6Clo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies.
Authors
Keehoon Jung, Takahiro Heishi, Omar F. Khan, Piotr S. Kowalski, Joao Incio, Nuh N. Rahbari, Euiheon Chung, Jeffrey W. Clark, Christopher G. Willett, Andrew D. Luster, Seok Hyun Yun, Robert Langer, Daniel G. Anderson, Timothy P. Padera, Rakesh K. Jain, Dai Fukumura
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)