Interleukin-10 overexpression in 4T1 cells: A gateway to suppressing mammary carcinoma growth
Xiaoqin Wang, Xiaoqian Wang, Dan Wang, Can Zhou, Kaige Lv, Yanfen Ma, Yanfen Ma, Wenjing Chang, Baofeng Wang, Hu Jian, Yanhong Ji, Zhijun Dai, Yunfeng Ma, Yunfeng Ma
Abstract
• IL-10 overexpression in TNBC suppresses tumor growth by increasing IFN-γ secreting CD8 + T cells and decreasing MDSCs in the tumor microenvironment. • Tumor-derived IL-10 reduces MDSCs infiltration through inhibition of myeloid cell differentiation and CXCL5 downregulation. • CXCL5 expression and MDSC infiltration correlate in human breast cancer, suggesting targeting the IL-10-CXCL5-MDSCs axis for immunotherapy. Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8 + T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8 + T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2 + MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8 + T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8 + T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8 + T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.