The Correlation Between IL-6/SOCS Signaling Pathway And The Infiltration And Accumulation Of MDSCs In Breast Cancer

Objective: This study is aimed to investigate the role of tumor-derived IL-6 in the infiltration and accumulation of MDSCs in breast cancer, and to determine if the defect of SOCSs expression is occured in MDSCs, and thus to explore the correlation between dysfunctional IL-6/SOCS signaling pathway and the infiltration and accumulation of MDSCs in breast cancer.Methods: 253 cases of primary breast cancer tumor samples were collected and the expression of IL-6 and the proportion of MDSCs in situ was detected using immumohistochemistry. The correlation between the level of IL-6 and the number of MDSCs was analyzed, as well as their relationship with respective clinical-pathological characteristics. Twenty cases of fresh breast invasive ductal carcinoma samples were collected and dissociated into single-cell suspension. Infiltrated MDSCs in cancer samples were enriched using human CD33 Micro Beads. The phenotypes of MDSCs were detected using flow cytometry. Quantitative real-time RT-PCR method was used to detect the m RNA expression of IL-6 in cancer tissues, and IL-6 receptors and SOCSs in MDSCs. The correlation among the expression of IL-6 in cancer, the proportion of MDSCs, the expression of IL-6 receptors and SOCSs in tumor-derived MDSCs was analyzed. The expression of IL-6 receptors and SOCSs in MDSCs and healthy immature myeloid-derived cells was compared.Results: Immumohistochemistry staining showed that IL-6 expression was detected in 65.6% of breast cancer samples, and infiltrated MDSCs were observed in 69.7% of breast cancer samples. More MDSCs infiltrated in IL-6 overexpressing breast cancer samples was observed(P<0.05). High IL-6 expression correlated with more lymph nodes invasion and more advanced pathological stage, but shorter OS(P<0.05). More MDSCs correlated with higher histological grade, more lymph nodes invasion, larger tumor size and more advanced pathological stage, but worse prognosis(P<0.05). IL-6high/MDSCshigh breast cancer patients had worse OS than others. Higher number of MDSCs was isolated from IL-6 overexpressing breast cancer samples than IL-6 low-expressing ones [(13.75±3.44)% vs.(4.31±1.50)%, P=0.03]. The levels of CD126, gp130, and SOCS1 significantly increased in MDSCs compared to those in healthy immature myeloid-derived cells(P<0.05). However, the level of SOCS3 significantly decreased in MDSCs compared to that in healthy immature myeloid-derived cells(P < 0.05). SOCS2 was undetected in both MDSCs and immture myeloid-derived cells. Furthermore, MDSCs isolated from IL-6 overexpressing breast cancer samples expressed higher CD126 and SOCS1, but lower SOCS3 than IL-6-low-expressing samples(P<0.05). No significant difference in the expression of gp130 was observed between the MDSCs isolated from either IL-6 overexpressing samples or low-expressing ones(P>0.05).Conclusion: Tumor-derived IL-6 was positively correlated with the accumulation of MDSCs in breast cancer. High number of MDSCs infiltrated in cancer tissues implied worse prognosis of breast cancer patients. Dysfunctional IL-6/SOCS signaling was present in breast cancer MDSCs, which was characterized by increased expresion of IL-6 receptors and defect of SOCS3 expression and significantly correlated with the infiltration and accumulation of MDSCs in breast cancer.