Abstract
Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+Gr-1−F4/80−MHCII− in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+Gr-1+ conventional MDSCs. Furthermore, sustained suppression of SOCS3 and aberrant hyperactivation of the JAK/STAT signaling pathway was exclusively detected in wide-type 4T1 tumor-bearing mice, which promoted the accumulation of e-MDSCs in situ and their immunosuppressive capability in vitro. After blocking the IL-6/STAT3 signaling pathway with the IL-6 receptor antibody or STAT3 antagonist JSI-124 in tumor-bearing mice, significant shrinkage of primary tumors and decrease in lung metastatic nodules were observed in vivo, accompanied by the dramatic decrease of e-MDSC recruitment and recovery of anti-tumor T cell immunity. Thus, SOCS3 suppression accelerated the IL-6-mediated growth and metastasis of mammary carcinoma via affecting myeloid differentiation in breast cancer. Moreover, the IL-6/STAT3 signaling pathway might be a promising candidate target in developing novel therapeutic strategies to eliminate e-MDSCs and improve breast cancer prognosis.
Highlights
Immune suppression is a major barrier to effective cancer immunotherapy, and the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism that promotes immune suppression
The 4T1WT, 4T1NC, and 4T1IL-6low cells were implanted into NOD/SCID mice separately, and the results showed that IL-6 knockdown inhibited tumor growth to some extent in T- and B-cell immunity-deficient mice (P = 0.001)
The results showed that Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), tyrosine kinase 2 (TYK2), Figure 2 | Effects of interleukin-6 (IL-6) knockdown in 4T1 cells in vitro. (A) Morphology of 4T1WT, 4T1NC, and 4T1IL-6low cells. (B) Cell growth was monitored by Cell
Summary
Immune suppression is a major barrier to effective cancer immunotherapy, and the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism that promotes immune suppression. MDSCs are a heterogeneous population of immature myeloid cells found within tumor microenvironments that exert suppressive effects on both innate and adaptive immunity [1,2,3]. Their phenotypes in cancer are rather diverse. Similar cell subsets (M-MDSCs and PMN-MDSCs) were detected with distinct phenotypes of CD11b+HLA-DR−/loCD14+CD15− and CD11b+HLA-DR−/loCD14−CD15+, respectively [5]. “early-stage MDSCs” (e-MDSCs) with the phenotype of Lin−HLADR−CD33+, which comprise more immature progenitors, have been defined as the third subset of human MDSCs [6]. Its counterpart in mice and the development of e-MDSCs have still not been disclosed
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