The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer
The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer
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DOI：
10.1007/s00262-020-02628-2
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发表时间：
2020-06-19
影响因子：
5.8
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
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作者：
Komura, Naoko;Mabuchi, Seiji;Kimura, Tadashi
本研究的目的是研究骨髓来源的抑制细胞（MDSC）在诱导卵巢癌中的癌症干细胞样细胞（CSC）和程序性死亡配体1（PD-L1）表达中的作用。CSC定义为高水平表达醛脱氢酶1（ALDH 1）的肿瘤细胞。我们将表达G-CSF或表达Mock的卵巢癌细胞接种到小鼠体内，并通过流式细胞术比较这些模型肿瘤中MDSC和CSC的频率。为了直接证明MDSC在CSC诱导和PD-L1表达增加中的作用，我们进行了体外共培养。MDSC和CSC（ALDH高细胞）在表达G-CSF的细胞来源的肿瘤中比在表达Mock的细胞来源的肿瘤中更常见。共培养实验表明，MDSC通过产生PGE 2增加CSC的数量。此外，在卵巢癌细胞中，MDSC产生的PGE 2通过哺乳动物雷帕霉素靶蛋白（mTOR）途径增加肿瘤PD-L1表达。在卵巢癌细胞与MDSC共培养的体外实验中，观察到CSC中PD-L1的表达高于非CSC（ALDH低细胞）。此外，通过免疫荧光染色，我们发现PD-L1与ALDH 1在体内小鼠模型中共表达。总之，由MDSC产生的PGE 2增加了上皮性卵巢癌中的干细胞样特性和肿瘤PD-L1表达。耗尽MDSC可能通过减少CSC数量和肿瘤PD-L1表达而对卵巢癌有效。
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.