PMID- 32561967 OWN - NLM STAT- MEDLINE DCOM- 20201207 LR - 20240426 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 69 IP - 12 DP - 2020 Dec TI - The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer. PG - 2477-2499 LID - 10.1007/s00262-020-02628-2 [doi] AB - 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. FAU - Komura, Naoko AU - Komura N AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Mabuchi, Seiji AU - Mabuchi S AUID- ORCID: 0000-0003-1803-1166 AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. smabuchi@naramed-u.ac.jp. AD - Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara, 634-8522, Japan. smabuchi@naramed-u.ac.jp. FAU - Shimura, Kotaro AU - Shimura K AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Yokoi, Eriko AU - Yokoi E AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Kozasa, Katsumi AU - Kozasa K AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Kuroda, Hiromasa AU - Kuroda H AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Takahashi, Ryoko AU - Takahashi R AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Sasano, Tomoyuki AU - Sasano T AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Kawano, Mahiru AU - Kawano M AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Matsumoto, Yuri AU - Matsumoto Y AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Kodama, Michiko AU - Kodama M AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Hashimoto, Kae AU - Hashimoto K AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Sawada, Kenjiro AU - Sawada K AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. FAU - Kimura, Tadashi AU - Kimura T AD - Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. LA - eng GR - T17K112760/Grants-in-aid for General Scientific Research/ GR - A19K213480/Grants-in-aid for General Scientific Research/ GR - A19K186410/Grants-in-aid for General Scientific Research/ PT - Journal Article DEP - 20200619 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (B7-H1 Antigen) RN - 143011-72-7 (Granulocyte Colony-Stimulating Factor) RN - EC 1.2.1 (Aldehyde Dehydrogenase 1 Family) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Aldehyde Dehydrogenase 1 Family/metabolism MH - Animals MH - Antineoplastic Agents, Immunological/pharmacology/therapeutic use MH - B7-H1 Antigen/immunology/*metabolism MH - Carcinoma, Ovarian Epithelial/drug therapy/*immunology/mortality/pathology MH - Cell Line, Tumor MH - Coculture Techniques MH - Dinoprostone/metabolism MH - Female MH - Granulocyte Colony-Stimulating Factor/genetics/metabolism MH - Humans MH - Mice MH - Middle Aged MH - Myeloid-Derived Suppressor Cells/drug effects/*immunology MH - Neoplastic Stem Cells/*immunology/metabolism MH - Ovarian Neoplasms/drug therapy/*immunology/mortality/pathology MH - Prognosis MH - Progression-Free Survival MH - Xenograft Model Antitumor Assays PMC - PMC11027471 OTO - NOTNLM OT - Cancer stem cell OT - Myeloid-derived suppressor cells OT - Ovarian cancer OT - Programmed death ligand 1 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/06/21 06:00 MHDA- 2020/12/15 06:00 PMCR- 2020/06/19 CRDT- 2020/06/21 06:00 PHST- 2020/01/27 00:00 [received] PHST- 2020/05/28 00:00 [accepted] PHST- 2020/06/21 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/06/21 06:00 [entrez] PHST- 2020/06/19 00:00 [pmc-release] AID - 10.1007/s00262-020-02628-2 [pii] AID - 2628 [pii] AID - 10.1007/s00262-020-02628-2 [doi] PST - ppublish SO - Cancer Immunol Immunother. 2020 Dec;69(12):2477-2499. doi: 10.1007/s00262-020-02628-2. Epub 2020 Jun 19.