The prognostic value of myeloid derived suppressor cell level in hepatocellular carcinoma: A systematic review and meta-analysis

Autoři: Xinyu Zhang aff001;  Xin Fu aff001;  Tianyu Li aff001;  Huimin Yan aff002
Působiště autorů: Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei, China aff001;  Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225327


Background and aims

Many studies have investigated the association between the level of myeloid derived suppressor cells (MDSCs) and clinical features and prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. This systematic review and meta-analysis was conducted to summarize all available data and estimate the relationship.


A comprehensive literature review was carried out using Medline, Embase and Web of Science database through December 2018 to identify relevant studies. The standardized mean difference (SMD) and the hazard ratio (HR) with 95% confidence interval (CI) were utilized for evaluating continuous outcomes and survival analysis, respectively. All statistical analyses were performed by STATA 14.0 software.


A total of 13 studies with 1002 HCC patients were included in the meta-analysis. Overall, the proportion of MDSCs in HCC patients was higher than that in healthy controls (SMD = 4.49, 95% CI = 2.53–6.46, P<0.001), and patients with chronic liver disease (SMD = 3.41, 95% CI = 1.58–5.24, P<0.001). Subgroup analysis based on the phenotypes of MDSCs and geographical areas showed similar results. However, the frequency of MDSCs was not affected by the treatment with conventional approaches for HCC (SMD = -0.25, 95% CI = -0.57–0.06, P = 0.119). Moreover, increased MDSCs level was significantly associated with poorer overall survival (HR = 2.36, 95% CI = 1.70–3.29, P<0.001) and recurrence-free survival (HR = 2.72, 95% CI = 1.70–4.35, P<0.001), but not significantly correlated with any clinicopathological parameters.


The results of this systematic review suggest that elevated MDSCs level appears to be associated with an increased risk for disease progression and poor prognosis for HCC.

Klíčová slova:

Cancer treatment – Database searching – Fluorescence-activated cell sorting – Hepatocellular carcinoma – Chronic liver disease – Prognosis – Publication ethics


1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492 30207593

2. Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh MP. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog. 2019;128:184–194. doi: 10.1016/j.micpath.2019.01.004 30611768

3. Roth GS, Decaens T. Liver immunotolerance and hepatocellular carcinoma: Patho-physiological mechanisms and therapeutic perspectives. Eur J Cancer. 2017;87:101–112. doi: 10.1016/j.ejca.2017.10.010 29145036

4. Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–232. doi: 10.1038/s41590-018-0044-z 29379119

5. Gabrilovich D, Nagaraj S. Myeloid-derived-suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9:162–174. doi: 10.1038/nri2506 19197294

6. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 2015;128:95–139. doi: 10.1016/bs.acr.2015.04.002 26216631

7. Tian T, Gu X, Zhang B, Liu Y, Yuan C, Shao L, Guo Y, Fan K. Increased circulating CD14(+)HLA-DR-/low myeloid-derived suppressor cells are associated with poor prognosis in patients with small-cell lung cancer. Cancer Biomark. 2015;15(4):425–432. doi: 10.3233/CBM-150473 25792471

8. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–119. doi: 10.1038/s41590-017-0022-x 29348500

9. Mao FY, Zhao YL, Lv YP, Teng YS, Kong H, Liu YG, Wu XL, Hao CJ, Chen W, Duan MB, Han B, Ma Q, Wang TT, Peng LS, Zhang JY, Cheng P, Su CY, Fu XL, Zou QM, Guo G, Guo XL, Zhuang Y. CD45+CD33lowCD11bdim myeloid-derived suppressor cells suppress CD8+ T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer. Cell Death Dis. 2018;9(7):763. doi: 10.1038/s41419-018-0803-7 29988030

10. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother. 2013;62(8):1421–1430. doi: 10.1007/s00262-013-1447-1 23764929

11. Chiu DK, Tse AP, Xu IM, Di Cui J, Lai RK, Li LL, Koh HY, Tsang FH, Wei LL, Wong CM, Ng IO, Wong CC. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Nat Commun. 2017;8(1):517. doi: 10.1038/s41467-017-00530-7 28894087

12. Hetta HF, Zahran AM, Mansor SG, Abdel-Malek MO, Mekky MA, Abbas WA. Frequency and Implications of myeloid-derived suppressor cells and lymphocyte subsets in Egyptian patients with hepatitis C virus-related hepatocellular carcinoma. J Med Virol. 2019 Jul;91(7):1319–1328. doi: 10.1002/jmv.25428 30761547

13. Wang J, Yang J. Identification of CD4+CD25+CD127- regulatory T cells and CD14+HLA-DR-/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer. Biomed Rep. 2016;5(2):208–212. doi: 10.3892/br.2016.694 27446543

14. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. doi: 10.1186/1745-6215-8-16 17555582

15. Herzog R, Alvarez-Pasquin MJ, Diaz C, Del Barrio JL, Estrada JM, Gil A. Are healthcare workers' intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review. BMC Public Health. 2013;13:154. doi: 10.1186/1471-2458-13-154 23421987

16. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, Greten TF, Korangy F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008;135(1):234–243. doi: 10.1053/j.gastro.2008.03.020 18485901

17. Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, Kagaya T, Yamashita T, Fushimi K, Kaneko S. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013;57(4):1448–1457. doi: 10.1002/hep.26153 23174905

18. Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013;73(8):2435–2444. doi: 10.1158/0008-5472.CAN-12-3381 23423978

19. Wang D, An G, Xie S, Yao Y, Feng G. The clinical and prognostic significance of CD14(+)HLA-DR(-/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol. 2016;37(8):10427–10433. doi: 10.1007/s13277-016-4916-2 26846107

20. Mizukoshi E, Yamashita T, Arai K, Terashima T, Kitahara M, Nakagawa H, Iida N, Fushimi K, Kaneko S. Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma. Cancer Immunol Immunother. 2016;65(6):715–725. doi: 10.1007/s00262-016-1837-2 27083166

21. Kalathil SG, Lugade AA, Miller A, Iyer R, Thanavala Y. PD-1+ and Foxp3+ T cell reduction correlates with survival of HCC patients after sorafenib therapy. JCI Insight. 2016;1(11). pii: e86182. doi: 10.1172/jci.insight.86182 27540594

22. Iwata T, Kondo Y, Kimura O, Morosawa T, Fujisaka Y, Umetsu T, Kogure T, Inoue J, Nakagome Y, Shimosegawa T. PD-L1+MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci Rep. 2016;6:39296. doi: 10.1038/srep39296 27966626

23. Gao XH, Tian L, Wu J, Ma XL, Zhang CY, Zhou Y, Sun YF, Hu B, Qiu SJ, Zhou J, Fan J, Guo W, Yang XR. Circulating CD14+ HLA-DR-/low myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery. Hepatol Res. 2017;47(10):1061–1071. doi: 10.1111/hepr.12831 27764536

24. Deng Y, Cheng J, Fu B, Liu W, Chen G, Zhang Q, Yang Y. Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene. 2017;36(8):1090–1101. doi: 10.1038/onc.2016.273 27593937

25. Li X, Xing YF, Lei AH, Xiao Q, Lin ZH, Hong YF, Wu XY, Zhou J. Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients. Oncotarget. 2017;8(15):24380–24388. doi: 10.18632/oncotarget.15456 28412745

26. Zhou J, Liu M, Sun H, Feng Y, Xu L, Chan AWH, Tong JH, Wong J, Chong CCN, Lai PBS, Wang HK, Tsang SW, Goodwin T, Liu R, Huang L, Chen Z, Sung JJ, Chow KL, To KF, Cheng AS. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut. 2018;67(5):931–944. doi: 10.1136/gutjnl-2017-314032 28939663

27. Elwan N, Salem ML, Kobtan A, El-Kalla F, Mansour L, Yousef M, Al-Sabbagh A, Zidan AA, Abd-Elsalam S. High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients. Immunol Invest. 2018;47(2):169–180. doi: 10.1080/08820139.2017.1407787 29182438

28. Sarhan D, Cichocki F, Zhang B, Yingst A, Spellman SR, Cooley S, Verneris MR, Blazar BR, Miller JS. Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res. 2016;76(19):5696–5706. doi: 10.1158/0008-5472.CAN-16-0839 27503932

29. Ben-Meir K, Twaik N, Baniyash M. Plasticity and biological diversity of myeloid derived suppressor cells. Curr Opin Immunol. 2018;51:154–161. doi: 10.1016/j.coi.2018.03.015 29614426

30. Su L, Xu Q, Zhang P, Michalek SM, Katz J. Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection. Infect Immun. 2017;85(8):e00213–17. doi: 10.1128/IAI.00213-17 28533469

31. Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother. 2012;61(8):1155–1167. doi: 10.1007/s00262-012-1294-5 22692756

32. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356–3364. doi: 10.1172/JCI80005 26168215

33. Hirbod-Mobarakeh A, Mirghorbani M, Hajiju F, Marvi M, Bashiri K, Rezaei N. Myeloid-derived suppressor cells in gastrointestinal cancers: A systematic review. J Gastroenterol Hepatol. 2016;31(7):1246–1256. doi: 10.1111/jgh.13284 26729006

34. Zhang S, Ma X, Zhu C, Liu L, Wang G, Yuan X. The Role of Myeloid-Derived Suppressor Cells in Patients with Solid Tumors: A Meta-Analysis. PLoS One. 2016;11(10):e0164514. doi: 10.1371/journal.pone.0164514 27780254

35. Wang PF, Song SY, Wang TJ, Ji WJ, Li SW, Liu N, Yan CX. Prognostic role of pretreatment circulating MDSCs in patients with solid malignancies: A meta-analysis of 40 studies. Oncoimmunology. 2018;7(10):e1494113. doi: 10.1080/2162402X.2018.1494113 30288362

Článek vyšel v časopise


2019 Číslo 12