IL-17-CXCR2 axis promotes breast cancer metastasis and therapy resistance through facilitating recruitment of neutrophils

Breast cancer is one of the most common cancer types that happens to global females. The major challenges for breast cancer include therapy resistance and metastasis. Various factors and cancer-related immune cells are involved in tumor chemotherapy resistance process, including pro-inflammatory cytokine, interleukin (IL) 17, CXCR2 ligands (pro-inflammatory chemokines) and neutrophils. They are the key players for promoting cancer progression, and numerous reports indicated them as a potential therapeutic target for various cancer types including breast cancer. However, the detailed mechanism(s) remains unclear. In the present study, we investigate the role of neutrophils in chemotherapy resistance and metastasis in breast cancer. In our previous study, we have observed increased levels of CXCR2 ligands in chemotherapy-resistant cells comparing with Cl66 parent cells. In this study, we observed upregulated IL17, IL17 receptor (IL-17R), granulocyte colony stimulating factor (GCSF) by qRT- PCR in resistant cells compared with parent cells. We further evaluated the protein levels of CXCR2 and its ligands, IL17 and its receptor, frequencies of neutrophils and T-helper 17 (Th17) cells in primary and metastatic tumors through using immunohistochemistry method. There were higher levels of IL17R, CXCR2, and CXCR2 ligands in metastatic tumor sites in comparison to the primary tumor sites. Moreover, we observed increased levels of IL17R, CXCR2, CXCR2 ligands together with the higher frequencies of neutrophils and Th17 cells in resistant tumors than Cl66 tumors. At the same time, tumor cells treated with IL-17 increased its proliferation rate and its expression of CXCL1 & CXCL5; and the increase was all in a concentration-dependent manner. In addition, the increase of CXCR2 ligands by IL17 was inhibited when we treated the tumor cells with ERK and NF-KB signaling inhibitors, indicating both pathways are involved in the regulation of IL17-induced CXCR2 ligands secretion. Together, our data demonstrate an IL17-CXCR2 ligands axis plays protumorigenic inflammation, facilitating therapy resistance and metastasis through recruited neutrophils. Citation Format: Lingyun Wu, Sugandha Saxena, Mohammad Awaji, Bhawna Sharma, Rakesh Singh. IL-17-CXCR2 axis promotes breast cancer metastasis and therapy resistance through facilitating recruitment of neutrophils [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4554.