RRC ID 60797
Author Komura N, Mabuchi S, Shimura K, Yokoi E, Kozasa K, Kuroda H, Takahashi R, Sasano T, Kawano M, Matsumoto Y, Kodama M, Hashimoto K, Sawada K, Kimura T.
Title The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer.
Journal Cancer Immunol Immunother
Abstract The aim of this study was to investigate the role of myeloid-derived suppressor cells (MDSC) in the induction of cancer stem-like cells (CSC) and programmed death ligand 1 (PD-L1) expression in ovarian cancer. CSC were defined as tumor cells expressing high levels of aldehyde dehydrogenase 1 (ALDH 1). We inoculated G-CSF-expressing or Mock-expressing ovarian cancer cells into mice, and the frequencies of MDSC and CSC in tumors of these models were compared by flow cytometry. To directly demonstrate the role of MDSC in the induction of CSC and the increase in PD-L1 expression, we performed in vitro co-culture. MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.
Volume 69(12)
Pages 2477-2499
Published 2020-12-1
DOI 10.1007/s00262-020-02628-2
PII 10.1007/s00262-020-02628-2
PMID 32561967
MeSH Aldehyde Dehydrogenase 1 Family / metabolism Animals Antineoplastic Agents, Immunological / pharmacology Antineoplastic Agents, Immunological / therapeutic use B7-H1 Antigen / immunology B7-H1 Antigen / metabolism* Carcinoma, Ovarian Epithelial / drug therapy Carcinoma, Ovarian Epithelial / immunology* Carcinoma, Ovarian Epithelial / mortality Carcinoma, Ovarian Epithelial / pathology Cell Line, Tumor Coculture Techniques Dinoprostone / metabolism Female Granulocyte Colony-Stimulating Factor / genetics Granulocyte Colony-Stimulating Factor / metabolism Humans Mice Middle Aged Myeloid-Derived Suppressor Cells / drug effects Myeloid-Derived Suppressor Cells / immunology* Neoplastic Stem Cells / immunology* Neoplastic Stem Cells / metabolism Ovarian Neoplasms / drug therapy Ovarian Neoplasms / immunology* Ovarian Neoplasms / mortality Ovarian Neoplasms / pathology Prognosis Progression-Free Survival Xenograft Model Antitumor Assays
IF 5.442
Times Cited 0
DNA material pCAmGCSF (RDB01522) pCAZ 2 (RDB01870)
Human and Animal Cells OV2944-HM-1(RCB1483)