| Autor: |
Wenwen Zhang, Xingchen Li, Mengmeng Jiang, Chenyan Ji, Guidong Chen, Qiaoling Zhang, Pengpeng Liu, Rui Zhang, Xiubao Ren, Wenwen Yu, Jinpu Yu |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Journal of Leukocyte Biology. 113:445-460 |
| ISSN: |
1938-3673 |
| DOI: |
10.1093/jleuko/qiad020 |
| Popis: |
Early-stage myeloid-derived suppressor cells are a newly defined subset of myeloid-derived suppressor cells in breast cancer tissues and related to poor prognosis in patients with breast cancer. Compared with classical myeloid-derived suppressor cells, early-stage myeloid-derived suppressor cells display exceptional immunosuppressive ability and accumulate in the tumor microenvironment to suppress innate and adaptive immunity. Previously, we demonstrated that early-stage myeloid-derived suppressor cells were SOCS3 deficiency dependent and correlated with differentiation arrest in the myeloid lineage. Autophagy is a major regulator of myeloid differentiation, but the mechanism by which autophagy regulates the development of early-stage myeloid-derived suppressor cells has not been elucidated. Here, we constructed EO771 mammary tumor-bearing conditional myeloid SOCS3 knockout mice (SOCS3MyeKO) characterized by abundant tumor-infiltrating early-stage myeloid-derived suppressor cells and exacerbated immunosuppression in vitro and in vivo. We found that early-stage myeloid-derived suppressor cells 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 microRNA microarray assays revealed that miR-155–induced C/EBPβ downregulation activated the Wnt/mTOR pathway and promoted autophagy repression and differentiation arrest in early-stage myeloid-derived suppressor cells. Furthermore, inhibition of Wnt/mTOR signaling suppressed both tumor growth and the immunosuppressive functions of early-stage myeloid-derived suppressor cells. 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 early-stage myeloid-derived suppressor cell survival, which might shed new light on a potential target of oncologic therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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