Abstract 175: Tumor-associated monocytes and neutrophils: Targets for immunotherapy

Abstract Cancer is the leading cause of deaths worldwide. However, current anti-VEGF therapies for solid cancers provide limited survival benefit as tumors rapidly develop resistance to these agents. We have uncovered an immunosuppressive role for non-classical Ly6Clow monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following the VEGF signaling blockade, resulting in recruitment of CX3CR1+ Ly6Clow monocytes into the tumor. We also found that treatment with VEGF-A reduced expression of CX3CL1 in endothelial cells. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clow monocyte transmigration across the endothelium in tumors. Moreover, Ly6Clow monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clowmonocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, we developed a gene therapy using a nanoparticle formulated with a siRNA against CX3CL1, which reduced Ly6Clow monocyte recruitment and improved outcome of anti-VEGFR2 therapy. Taken together, we identified immunosuppressive non-classical Ly6Clow monocytes as key players in tumor resistance to anti-angiogenic therapy in cancers. We also revealed molecular mechanisms underlying anti-angiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies, proven by state-of-the-art in vivo imaging modalities. Citation Format: Keehoon Jung. Tumor-associated monocytes and neutrophils: Targets for immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 175.