Abstract 5081: IL-6 trans-signaling pathway promotes early-stage myeloid derived suppressor cells (eMDSCs) via SOCS3 suppression in breast cancer

Abstract

Abstract IL-6 is known to be an important trigger of the expansion and recruitment of myeloid-derived suppressor cells (MDSCs) which are regarded as major coordinators of immunosuppressive microenvironment in cancer. But key molecular events are not fully understood yet. We previously identified a subset of early-stage MDSCs (eMDSCs) with immature myeloid phenotypes in IL-6 over-expressing breast cancer tissues. In this study we elucidated how tumor-derived IL-6 manipulated the development and function of eMDSCs in vitro and vivo. We isolated primary eMDSCs in situ and induced eMDSCs in vitro separately, as well as constructed IL-6 knockdown 4T1 mammary tumor-bearing mice models to explore the molecular events involved. We found that in primary human breast cancer tissues, tumor-derived IL-6 was positively correlated with the accumulation of eMDSCs in situ, which in turn accelerated tumor progression and unfavorable clinical outcomes. IL-6 significantly stimulated the amplification of eMDSCs and promoted their T cell suppressive capacity in vitro. And IL-6 trans-signaling pathway via soluble IL-6 receptor CD126 induced SOCS3 suppression and aberrant hyperphosphorylation of the JAK/STAT signaling pathway in eMDSCs, which promoted the accumulation of eMDSCs in vitro and vivo. Correspondingly, we defined a similar immature subset of CD11b+Gr-1- eMDSCs in IL-6 over-expressing 4T1 murine mammary cancer-bearing mice which displayed more potent suppression on T cell immunity than conventional CD11b+Gr-1+ MDSCs. The proportion of CD11b+Gr-1- eMDSCs in tumor tissues was highly correlated with the tumor size and the numbers of lung metastatic nodules compared to the CD11b+Gr-1+ MDSCs. Tumor-derived IL-6 inducing the inhibition of SOCS3 and the activation of the JAK/STAT signaling pathway was observed in CD11b+Gr-1- MDSCs simultaneously, which further caused the differentiation arrest of myeloid linkage and comparable immunosuppressive capacity of eMDSCs. In order to inhibit IL-6-triggerd activation of the JAK/STAT pathway, specific IL-6R blocking antibody and STAT antagonist JSI-124 were prescribed to 4T1 tumor-bearing mice. We found significant shrinkage of primary tumor and decrease of lung metastatic nodules in vivo, along with recovery of the differentiation of myeloid linkage and attenuation of eMDSC-mediated T cell suppression in vitro. Therefore, we concluded that IL-6-induced dysfunction of the SOCS feedback loop and hyperactivation of the JAK/STAT signaling pathway produced significant differentiation arrest in myeloid linkage, which promoted the accumulation of eMDSCs, the defect in local immune surveillance, and consequential tumor progression in breast cancer. Target therapy against this pathway efficiently decelerated the growth and metastasis of breast cancer in vivo which might be a promising therapeutic strategy for breast cancer treatment. Citation Format: Jinpu Yu. IL-6 trans-signaling pathway promotes early-stage myeloid derived suppressor cells (eMDSCs) via SOCS3 suppression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5081.