LAUSR

Early-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of MDSCs in breast cancer tissues, and was related to poor prognosis of breast cancer patients. Compared with classical MDSCs, eMDSCs display exceptional immunosuppressive ability and accumulate in the tumor microenvironment to suppress innate and adaptive immunity. Previously, we demonstrated that eMDSCs was SOCS3 deficiency-dependent and correlated with differentiation arrest in the myeloid lineage. Autophagy is a major regulator of myeloid differentiation, however, the mechanism by which autophagy regulate the development of eMDSCs has not been elucidated. Here, we constructed EO771 mammary tumor-bearing conditional myeloid SOCS3 knockout mice (SOCS3MyeKO) characterized by abundant tumor-infiltrating eMDSCs and exacerbated immunosuppression in vitro and in vivo. We found that eMDSCs isolated from SOCS3MyeKO mice showed differentiation arrest in the myeloid lineage, which was caused by limited autophagy activation in an Wnt/mTOR-dependent manner. RNA sequencing and miRNA microarray assays revealed that miR-155-induced C/EBPβ downregulation activated the Wnt/mTOR pathway, and promoted autophagy repression and differentiation arrest in eMDSCs. Furthermore, inhibition of Wnt/mTOR signaling suppressed both tumor growth and the immunosuppressive functions of eMDSCs. Thus, SOCS3 deficiency-dependent autophagy repression and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for promoting eMDSCs survival, which might shed new light on a potential target of oncologic therapy.