Abstract 1475: Blockade of IL17-GCSF-Bv8 inflammation axis ameliorate resistant to anti-angiogenic therapy for colon cancer

Abstract

Abstract Anti-angiogenic therapy in combination with chemotherapy is one of the standard strategies for metastatic/unresectable colon cancers. Therefore, resistance to anti-angiogenic therapy causes a critical problem for the treatment of colon cancer patients. While some resistant mechanisms of anti-angiogenic therapy were proposed, it is not yet completely unveiled. The aim of this study was to investigate the resistant mechanism against anti-angiogenic therapy using spontaneous colon cancer mouse models. We established a mouse model of anti-VEGF resistant colon cancer. Genetically-engineered Apc/Smad4 knockout mice developed several intestinal tumors that are sensitive to anti-VEGF neutralizing antibody. When Apc/Smad4 mice were treated with dextran sulfate sodium (DSS) (DSS-Apc/Smad4 mice), they developed colon tumors that were resistant to anti-VEGF antibody. Sera from DSS-Apc/Smad4 mice showed significant upregulation of granulocyte-colony stimulating factor (GCSF) compared to water-drinking Apc/Smad4 mice. Colon tumors from DSS-Apc/Smad4 mice also showed GCSF upregulation. It also showed upregulation of IL17, one of inflammatory cytokines upstream of GCSF, and Bv8, one of angiogenic factors downstream of GCSF, suggesting that IL17-GCSF-Bv8 inflammation axis contributes to obtaining anti-VEGF resistant. Immunostaining of the tumors from DSS-Apc/Smad4 mice revealed significant accumulation of neutrophils in the tumors. Neutrophils from tumor-bearing mice showed upregulation of Bv8 expression when stimulated with GCSF. Immunostaining confirmed that neutrophils in the tumors were positive for Bv8. When DSS-Apc/Smad4 mice were treated with either anti-IL17, anti-GCSF, or anti-BV8 neutralizing antibody in combination with anti-VEGF antibody, colonic tumor formation was significantly suppressed. We also performed ELISA analysis using human serum samples from subcohort of AVF2107 trial in which metastatic colon cancer patients were treated with chemotherapy (IFL with or without bevacizumab). Higher Bv8 serum levels by ELISA were significantly correlated with poor overall survival in human colon cancer patients. Collectively, inflammatory neutrophils in the tumor microenvironment of colon cancer provide anti-VEGF resistant through IL17-GCSF-Bv8 axis, and blockade of this pathway ameliorate resistance to anti-angiogenic therapy of colon cancer mouse models. Citation Format: Yoshiro Itatani, Takamasa Yamamoto, Napoleone Ferrara. Blockade of IL17-GCSF-Bv8 inflammation axis ameliorate resistant to anti-angiogenic therapy for colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1475.