The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer

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.

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Abbreviations

ALDH-1:

Aldehyde dehydrogenase 1

CSC:

Cancer stem-like cells

mTOR:

The mammalian target of rapamycin

PD-L1:

Programmed death ligand 1

TRL:

Tumor-related leukocytosis

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Acknowledgements

The authors thank Hirofumi Hamada (Sapporo Medical University) for providing information regarding the G-CSF expression plasmids. We also thank Moe Matsui for her secretarial assistance and Ayako Okamura for her technical assistance.

Funding

This study was funded by Grants-in-aid for General Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant Numbers: T17K112760, A19K213480 and A19K186410).

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Contributions

NK designed and performed the experiments, collected, analyzed and interpreted data, and wrote the manuscript. SM designed the experiments, interpreted data, and wrote the manuscript. KS, EY, KK, and HK performed the experiments and acquired the clinical data. RT, TS, MK, and YM contributed to development of methodology. MK, KH, and KS provided conceptual advice and interpreted data. TK edited the manuscript.

Corresponding author

Correspondence to Seiji Mabuchi.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards (Osaka University Hospital, Approval Number: 10302).

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Komura, N., Mabuchi, S., Shimura, K. et al. The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer. Cancer Immunol Immunother 69, 2477–2499 (2020). https://doi.org/10.1007/s00262-020-02628-2

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Keywords

  • Ovarian cancer
  • Myeloid-derived suppressor cells
  • Cancer stem cell
  • Programmed death ligand 1