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


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7



Aldehyde dehydrogenase 1


Cancer stem-like cells


The mammalian target of rapamycin


Programmed death ligand 1


Tumor-related leukocytosis


  1. 1.

    Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  CAS  Google Scholar 

  2. 2.

    Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY (2016) Ovarian cancer. Nat Rev Dis Primers 2:16061

    Article  Google Scholar 

  3. 3.

    Jayson GC, Kohn EC, Kitchener HC, Ledermann JA (2014) Ovarian cancer. Lancet 384:1376–1388

    Article  Google Scholar 

  4. 4.

    So KA, Hong JH, Jin HM et al (2014) The prognostic significance of preoperative leukocytosis in epithelial ovarian carcinoma: a retrospective cohort study. Gynecol Oncol 132:551–555

    Article  Google Scholar 

  5. 5.

    Chen Y, Zhang L, Liu WX, Liu XY (2015) Prognostic significance of preoperative anemia, leukocytosis and thrombocytosis in chinese women with epithelial ovarian cancer. Asian Pac J Cancer Prev 16:933–939

    Article  Google Scholar 

  6. 6.

    Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  CAS  Google Scholar 

  7. 7.

    Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296

    Article  CAS  Google Scholar 

  8. 8.

    Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

    Article  CAS  Google Scholar 

  9. 9.

    Ayub TH, Keyver-Paik MD, Debald M et al (2015) Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer. Oncotarget 6:16437–16448

    Article  Google Scholar 

  10. 10.

    Cui TX, Kryczek I, Zhao L et al (2013) Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39:611–621

    Article  CAS  Google Scholar 

  11. 11.

    Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213

    Article  CAS  Google Scholar 

  12. 12.

    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  CAS  Google Scholar 

  13. 13.

    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455

    Article  CAS  Google Scholar 

  14. 14.

    Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144

    Article  CAS  Google Scholar 

  15. 15.

    Lee Y, Shin JH, Longmire M et al (2016) CD44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin Cancer Res 22:3571–3581

    Article  CAS  Google Scholar 

  16. 16.

    Wu Y, Chen M, Wu P, Chen C, Xu ZP, Gu W (2017) Increased PD-L1 expression in breast and colon cancer stem cells. Clin Exp Pharmacol Physiol 44:602–604

    Article  CAS  Google Scholar 

  17. 17.

    Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752

    Article  CAS  Google Scholar 

  18. 18.

    Mabuchi S, Yokoi E, Komura N, Kimura T (2018) Myeloid-derived suppressor cells and their role in gynecological malignancies. Tumour Biol 40:1010428318776485

    Article  CAS  Google Scholar 

  19. 19.

    Peng D, Tanikawa T, Li W et al (2016) Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res 76(11):3156–3165

    Article  CAS  Google Scholar 

  20. 20.

    Kuroda H, Mabuchi S, Yokoi E et al (2018) Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer. Oncotarget 9:36317–36330

    Article  Google Scholar 

  21. 21.

    Yokoi E, Mabuchi S, Komura N et al (2019) The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations. Oncoimmunology 8:e1662708

    Article  Google Scholar 

  22. 22.

    Mabuchi S, Matsumoto Y, Kawano M et al (2014) Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature. J Natl Cancer Inst 106:dju147

    Article  CAS  Google Scholar 

  23. 23.

    Yoshida Y, Sadata A, Zhang W, Saito K, Shinoura N, Hamada H (1998) Generation of fiber-mutant recombinant adenoviruses for gene therapy of malignant glioma. Hum Gene Ther 9:2503

    Article  CAS  Google Scholar 

  24. 24.

    Samulski RJ, Srivastava A, Berns KI, Muzyczka N (1983) Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV. Cell 33:135–143

    Article  CAS  Google Scholar 

  25. 25.

    Kawano M, Mabuchi S, Matsumoto Y et al (2015) The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep 5:18217

    Article  CAS  Google Scholar 

  26. 26.

    Sasano T, Mabuchi S, Kozasa K et al (2018) The highly metastatic nature of uterine cervical/endometrial cancer displaying tumor-related leukocytosis: clinical and preclinical investigations. Clin Cancer Res 24:4018–4029

    Article  CAS  Google Scholar 

  27. 27.

    Mabuchi S, Altomare DA, Cheung M et al (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261–4270

    Article  CAS  Google Scholar 

  28. 28.

    Wang D, Fu L, Sun H, Guo L, DuBois RN (2015) Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology 149:1884–95.e4

    Article  CAS  Google Scholar 

  29. 29.

    Kurtova AV, Xiao J, Mo Q et al (2015) Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517:209–213

    Article  CAS  Google Scholar 

  30. 30.

    Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67(9):4507–4513

    Article  CAS  Google Scholar 

  31. 31.

    Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P (2011) Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118(20):5498–5505

    Article  CAS  Google Scholar 

  32. 32.

    Garcia-Diaz A, Shin DS, Moreno BH et al (2017) Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 19:1189–1201

    Article  CAS  Google Scholar 

  33. 33.

    Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48:434–452

    Article  CAS  Google Scholar 

  34. 34.

    Vo BT, Morton D Jr, Komaragiri S, Millena AC, Leath C, Khan SA (2013) TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology 154:1768–1779

    Article  CAS  Google Scholar 

  35. 35.

    Dufour M, Faes S, Dormond-Meuwly A, Demartines N, Dormond O (2014) PGE2-induced colon cancer growth is mediated by mTORC1. Biochem Biophys Res Commun 451:587–591

    Article  CAS  Google Scholar 

  36. 36.

    Weber J, Gibney G, Kudchadkar R et al (2016) Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol Res 4:345–353

    Article  CAS  Google Scholar 

  37. 37.

    Martens A, Wistuba-Hamprecht K, Geukes Foppen M et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22:2908–2918

    Article  CAS  Google Scholar 

  38. 38.

    Smyth MJ, Ngiow SF, Ribas A, Teng MW (2016) Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13:143–158

    Article  CAS  Google Scholar 

Download references


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.


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).

Author information




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.

Ethics declarations

Conflict of interest

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).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


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