Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

IRF7 regulates the development of granulocytic myeloid-derived suppressor cells through S100A9 transrepression in cancer

Oncogene volume 36, pages 2969–2980 (2017)Cite this article

Subjects

Abstract

Accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles against achieving appropriate anti-tumor immune responses and successful tumor immunotherapy. Granulocytic MDSCs (G-MDSCs) are common in tumor-bearing hosts. However, the mechanisms regulating the development of MDSCs, especially G-MDSCs, remain poorly understood. In this report, we showed that interferon regulatory factor 7 (IRF7) plays an important role in the development of G-MDSCs, but not monocytic MDSCs. IRF7 deficiency caused significant elevation of G-MDSCs, and therefore enhanced tumor growth and metastasis in mice. IRF7 deletion did not affect the suppressive activity of G-MDSCs. Mechanistic studies showed that S100A9, a negative regulator of myeloid cell differentiation, was transrepressed by the IRF7 protein. S100A9 knockdown almost completely abrogated the effects of IRF7 deletion on G-MDSC development and tumor metastasis. Importantly, IRF7 expression levels negatively correlated with the G-MDSC frequency and tumor metastasis, as well as S100A9 expression, in cancer patients. In summary, our study demonstrated that IRF7 represents a novel regulator of G-MDSC development in cancer, which may have predictive value for tumor progression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Gabrilovich DI, Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162–174.

    Article  CAS  Google Scholar 

  2. Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V . Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev 2008; 222: 162–179.

    Article  CAS  Google Scholar 

  3. Marvel D, Gabrilovich DI . Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015; 125: 3356–3364.

    Article  Google Scholar 

  4. Condamine T, Mastio J, Gabrilovich DI . Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol 2015; 98: 913–922.

    Article  CAS  Google Scholar 

  5. Waight JD, Netherby C, Hensen ML, Miller A, Hu Q, Liu S et al. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J Clin Invest 2013; 123: 4464–4478.

    Article  CAS  Google Scholar 

  6. Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest 2013; 123: 1580–1589.

    Article  CAS  Google Scholar 

  7. Capietto AH, Kim S, Sanford DE, Linehan DC, Hikida M, Kumosaki T et al. Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer. J Exp Med 2013; 210: 2257–2271.

    Article  CAS  Google Scholar 

  8. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 2010; 32: 790–802.

    Article  CAS  Google Scholar 

  9. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014; 211: 781–790.

    Article  CAS  Google Scholar 

  10. Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N et al. Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest 2014; 124: 2626–2639.

    Article  CAS  Google Scholar 

  11. Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P et al. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 2014; 41: 389–401.

    Article  CAS  Google Scholar 

  12. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI . Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008; 181: 5791–5802.

    Article  CAS  Google Scholar 

  13. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V . Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014; 1319: 47–65.

    Article  CAS  Google Scholar 

  14. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S et al. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 2010; 22: 238–244.

    Article  CAS  Google Scholar 

  15. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V . Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12: 253–268.

    Article  CAS  Google Scholar 

  16. Ning S, Pagano JS, Barber GN . IRF7: activation, regulation, modification and function. Genes Immun 2011; 12: 399–414.

    Article  CAS  Google Scholar 

  17. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005; 434: 772–777.

    Article  CAS  Google Scholar 

  18. Kim JK, Jin X, Ham SW, Lee SY, Seo S, Kim SC et al. IRF7 promotes glioma cell invasion by inhibiting AGO2 expression. Tumour Biol 2015; 36: 5561–5569.

    Article  CAS  Google Scholar 

  19. Zhang L, Zhang J, Lambert Q, Der CJ, Del Valle L, Miklossy J et al. Interferon regulatory factor 7 is associated with Epstein-Barr virus-transformed central nervous system lymphoma and has oncogenic properties. J Virol 2004; 78: 12987–12995.

    Article  CAS  Google Scholar 

  20. Bidwell BN, Slaney CY, Withana NP, Forster S, Cao Y, Loi S et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med 2012; 18: 1224–1231.

    Article  CAS  Google Scholar 

  21. Romieu-Mourez R, Solis M, Nardin A, Goubau D, Baron-Bodo V, Lin R et al. Distinct roles for IFN regulatory factor (IRF)-3 and IRF-7 in the activation of antitumor properties of human macrophages. Cancer Res 2006; 66: 10576–10585.

    Article  CAS  Google Scholar 

  22. Yu LX, Yan L, Yang W, Wu FQ, Ling Y, Chen SZ et al. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nat Commun 2014; 52: 5256.

    Article  Google Scholar 

  23. Mauti LA, Le Bitoux MA, Baumer K, Stehle JC, Golshayan D, Provero P et al. Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. J Clin Invest 2011; 121: 2794–2807.

    Article  CAS  Google Scholar 

  24. Condamine T, Ramachandran I, Youn JI, Gabrilovich DI . Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med 2015; 66: 97–110.

    Article  CAS  Google Scholar 

  25. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004; 6: 4094–21.

    Google Scholar 

  26. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008; 205: 2235–2249.

    Article  CAS  Google Scholar 

  27. Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna. G . Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 2008; 181: 4666–4675.

    Article  CAS  Google Scholar 

  28. Hibino T, Sakaguchi M, Miyamoto S, Yamamoto M, Motoyama A, Hosoi J et al. S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis. Cancer Res 2013; 73: 172–183.

    Article  CAS  Google Scholar 

  29. Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G . S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 2011; 9: 133–148.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Qin A, Cai W, Pan T, Wu K, Yang Q, Wang N et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J Virol 2013; 87: 1477–1490.

    Article  CAS  Google Scholar 

  32. Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ . Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 2013; 62: 1439–1451.

    Article  CAS  Google Scholar 

  33. 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: 2435–2444.

    Article  CAS  Google Scholar 

  34. Lu R, Pitha PM . Monocyte differentiation to macrophage requires interferon regulatory factor 7. J Biol Chem 2001; 276: 45491–45496.

    Article  CAS  Google Scholar 

  35. Foell D, Wittkowski H, Vogl T, Roth J . S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 2007; 81: 28–37.

    Article  CAS  Google Scholar 

  36. Clark HL, Jhingran A, Sun Y, Vareechon C, de Jesus CS, Skaar EP et al. Zinc and manganese chelation by neutrophil S100A8/A9 (calprotectin) limits extracellular aspergillus fumigatus hyphal growth and corneal infection. J Immunol 2016; 196: 336–344.

    Article  CAS  Google Scholar 

  37. Chernov AV, Dolkas J, Hoang K, Angert M, Srikrishna G, Vogl T et al. The calcium-binding proteins S100A8 and S100A9 initiate the early inflammatory program in injured peripheral nerves. J Biol Chem 2015; 290: 11771–11784.

    Article  CAS  Google Scholar 

  38. Wang L, Chang EW, Wong SC, Ong SM, Chong DQ, Ling KL . Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins. J Immunol 2013; 190: 794–804.

    Article  CAS  Google Scholar 

  39. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012; 150: 165–178.

    Article  CAS  Google Scholar 

  40. McNeill E, Hogg N . S100A9 has a protective role in inflammation-induced skin carcinogenesis. Int J Cancer 2014; 135: 798–808.

    Article  CAS  Google Scholar 

  41. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 2007; 450: 825–831.

    Article  CAS  Google Scholar 

  42. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096–1103.

    Article  CAS  Google Scholar 

  43. Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin Cytom 2015; 88: 77–91.

    Article  CAS  Google Scholar 

  44. Yang Q, Shi M, Shen Y, Cao Y, Zuo S, Zuo C et al. COX-1-derived thromboxane A2 plays an essential role in early B-cell development via regulation of JAK/STAT5 signaling in mouse. Blood 2014; 124: 1610–1621.

    Article  CAS  Google Scholar 

  45. Yang Q, Wei J, Zhong L, Shi M, Zhou P, Zuo S et al. Cross talk between histone deacetylase 4 and STAT6 in the transcriptional regulation of arginase 1 during mouse dendritic cell differentiation. Mol Cell Biol 2015; 35: 63–75.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the following grants to JZ: National Natural Science Foundation of China (No. 81571520; 91542112; and 31270921), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS, 2014), National Key Basic Research Program of China (No. 2012CB524900), Guangdong Innovative Research Team Program (No. 2009010058), The Fundamental Research Funds for the Central Universities, the Provincial Talents Cultivated by ‘Thousand-Hundred-Ten’ program of Guangdong Province, 111 Project (No. B12003).

Author information

Authors and Affiliations

  1. Program in Immunology, Affiliated Guangzhou Women and Children’s Medical Center, Zhongshan School of Medicine, Guangzhou, China

    Q Yang & J Zhou

  2. Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

    Q Yang, X Li, H Chen, Y Cao, Q Xiao, Y He, J Wei & J Zhou

  3. School of Basic Sciences, Guangzhou Medical University, Guangzhou, China

    Q Yang & J Zhou

  4. Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

    X Li

  5. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China

    J Zhou

Authors
  1. Q Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Q Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Zhou.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website .

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Q., Li, X., Chen, H. et al. IRF7 regulates the development of granulocytic myeloid-derived suppressor cells through S100A9 transrepression in cancer. Oncogene 36, 2969–2980 (2017). https://doi.org/10.1038/onc.2016.448

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.448

This article is cited by

Search

Advanced search

Quick links