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Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment

  • Suzanne Ostrand-RosenbergEmail author
  • Daniel W. Beury
  • Katherine H. Parker
  • Lucas A. Horn
Focussed Research Review

Abstract

Myeloid-derived suppressor cells (MDSC) are present in most cancer patients where they are significant contributors to the immune suppressive tumor microenvironment (TME). The TME is a hostile locale due to deficiencies in oxygen (hypoxia) and nutrients, and the presence of reactive oxygen species (ROS). The survival of tumor cells within the TME is partially governed by two mechanisms: (1) Activation of the transcription factor Nuclear Factor Erythroid-derived 2-like 2 (Nrf2) which turns on genes that attenuate oxidative stress; and (2) The presence of High Mobility Group Box Protein-1 (HMGB1), a damage-associated molecular pattern molecule (DAMP) that induces autophagy and protects against apoptosis. Because Nrf2 and HMGB1 promote tumor cell survival, we speculated that Nrf2 and HMGB1 may facilitate MDSC survival. We tested this hypothesis using Nrf2+/+ and Nrf2−/− BALB/c and C57BL/6 mice and pharmacological inhibitors of HMGB1. In vitro and in vivo studies demonstrated that Nrf2 increased the suppressive potency and quantity of tumor-infiltrating MDSC by up-regulating MDSC production of H2O2 and decreasing MDSC apoptosis. Decreased apoptosis was accompanied by a decrease in the production of MDSC, demonstrating that MDSC levels are homeostatically regulated. Pharmacological inhibition of autophagy increased MDSC apoptosis, indicating that autophagy increases MDSC half-life. Inhibition of HMGB1 also increased MDSC apoptosis and reduced MDSC autophagy. These results combined with our previous findings that HMGB1 drives the accumulation of MDSC demonstrate that HMGB1 maintains MDSC viability by inducing autophagy. Collectively, these findings identify Nrf2 and HMGB1 as important factors that enable MDSC to survive in the TME.

Keywords

MDSC Immune suppression Oxidative stress Autophagy High mobility group box protein 1 HMGB1 

Abbreviations

ARE

Anti-oxidant response elements

CBI

Checkpoint blockade inhibitors

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

DAMP

Damage-associated molecular pattern

HMGB1

High mobility group box protein 1

Keap1

Kelch-like ECH-associated protein 1

MDSC

Myeloid-derived suppressor cells

M-MDSC

Monocytic MDSC

mTOR

Mammalian target of rapamycin

Nrf2

Nuclear factor erythroid-2-related factor 2

PD-1

Programmed cell death protein 1

PD-L1

Programmed death-ligand 1

PI

Propidium iodide

PMN-MDSC

Polymorphonuclear or granulocytic MDSC

RAGE

Receptor for advanced glycation endproducts

ROS

Reactive oxygen species

TIMDSC

Tumor-infiltrating MDSC

tBHQ

Tert-butylhydroquinone

TME

Tumor microenvironment

Notes

Acknowledgements

The authors thank Ms. Virginia Clements for her outstanding technical support, and the undergraduate students at UMBC who participated in some of the original studies.

Author contributions

DWB, KHP, and LAH performed experiments. All authors developed the concepts, designed experiments, analyzed data, and wrote and edited the manuscript.

Funding

Original research described in this article was supported by US National Institutes of Health Grants R01CA84232, R01CA115880, and R01GM021248. Daniel W. Beury was partially supported by a US Department of Defense fellowship W81XWH-11-1-0115.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Research involving animals

Original research described in this article was approved by the UMBC Institutional Animal Care and Use Committee, protocol #SO01691417.

References

  1. 1.
    Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S (2019) Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 39:147–164.  https://doi.org/10.1200/EDBK_240837 CrossRefGoogle Scholar
  2. 2.
    Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268.  https://doi.org/10.1038/nri3175 CrossRefGoogle Scholar
  3. 3.
    Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506.  https://doi.org/10.4049/jimmunol.0802740 CrossRefGoogle Scholar
  4. 4.
    Parker KH, Beury DW, Ostrand-Rosenberg S (2015) Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 128:95–139.  https://doi.org/10.1016/bs.acr.2015.04.002 CrossRefGoogle Scholar
  5. 5.
    Ostrand-Rosenberg S, Fenselau C (2018) Myeloid-derived suppressor cells: immune-suppressive cells that impair antitumor immunity and are sculpted by their environment. J Immunol 200:422–431.  https://doi.org/10.4049/jimmunol.1701019 CrossRefGoogle Scholar
  6. 6.
    Ostrand-Rosenberg S (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68–75.  https://doi.org/10.1016/j.coi.2018.03.007 CrossRefGoogle Scholar
  7. 7.
    Clements VK, Long T, Long R, Figley C, Smith DMC, Ostrand-Rosenberg S (2018) Frontline science: high fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells. J Leukoc Biol 103:395–407.  https://doi.org/10.1002/JLB.4HI0517-210R CrossRefGoogle Scholar
  8. 8.
    Paardekooper LM, Vos W, van den Bogaart G (2019) Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget 10:883–896.  https://doi.org/10.18632/oncotarget.26608 CrossRefGoogle Scholar
  9. 9.
    Li Y, Patel SP, Roszik J, Qin Y (2018) Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational immunotherapy. Front Immunol 9:1591.  https://doi.org/10.3389/fimmu.2018.01591 CrossRefGoogle Scholar
  10. 10.
    Gouirand V, Guillaumond F, Vasseur S (2018) Influence of the tumor microenvironment on cancer cells metabolic reprogramming. Front Oncol 8:117.  https://doi.org/10.3389/fonc.2018.00117 CrossRefGoogle Scholar
  11. 11.
    Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, Hayes JD (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med 88:108–146.  https://doi.org/10.1016/j.freeradbiomed.2015.06.021 CrossRefGoogle Scholar
  12. 12.
    Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139.  https://doi.org/10.1128/MCB.24.16.7130-7139.2004 CrossRefGoogle Scholar
  13. 13.
    Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M (2004) Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci USA 101:2046–2051.  https://doi.org/10.1073/pnas.0308347100 CrossRefGoogle Scholar
  14. 14.
    Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322.  https://doi.org/10.1006/bbrc.1997.6943 CrossRefGoogle Scholar
  15. 15.
    Nguyen T, Huang HC, Pickett CB (2000) Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275:15466–15473.  https://doi.org/10.1074/jbc.M000361200 CrossRefGoogle Scholar
  16. 16.
    Panieri E, Saso L (2019) Potential applications of NRF2 inhibitors in cancer therapy. Oxid Med Cell Longev 2019:8592348.  https://doi.org/10.1155/2019/8592348 CrossRefGoogle Scholar
  17. 17.
    Zhu M, Fahl WE (2001) Functional characterization of transcription regulators that interact with the electrophile response element. Biochem Biophys Res Commun 289:212–219.  https://doi.org/10.1006/bbrc.2001.5944 CrossRefGoogle Scholar
  18. 18.
    Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, Shyr C, Wakabayashi N, Kensler TW, Wasserman WW, Biswal S (2010) Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38:5718–5734.  https://doi.org/10.1093/nar/gkq212 CrossRefGoogle Scholar
  19. 19.
    Wakabayashi N, Shin S, Slocum SL, Agoston ES, Wakabayashi J, Kwak MK, Misra V, Biswal S, Yamamoto M, Kensler TW (2010) Regulation of notch1 signaling by nrf2: implications for tissue regeneration. Sci Signal 3:ra52.  https://doi.org/10.1126/scisignal.2000762 CrossRefGoogle Scholar
  20. 20.
    Gonzalez Y, Aryal B, Chehab L, Rao VA (2014) Atg7- and Keap1-dependent autophagy protects breast cancer cell lines against mitoquinone-induced oxidative stress. Oncotarget 5:1526–1537.  https://doi.org/10.18632/oncotarget.1715 CrossRefGoogle Scholar
  21. 21.
    Wang J, Liu Z, Hu T, Han L, Yu S, Yao Y, Ruan Z, Tian T, Huang T, Wang M, Jing L, Nan K, Liang X (2017) Nrf2 promotes progression of non-small cell lung cancer through activating autophagy. Cell Cycle 16:1053–1062.  https://doi.org/10.1080/15384101.2017.1312224 CrossRefGoogle Scholar
  22. 22.
    Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477CrossRefGoogle Scholar
  23. 23.
    Kimmelman AC, White E (2017) Autophagy and Tumor Metabolism. Cell Metab 25:1037–1043.  https://doi.org/10.1016/j.cmet.2017.04.004 CrossRefGoogle Scholar
  24. 24.
    Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E (2006) Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10:51–64.  https://doi.org/10.1016/j.ccr.2006.06.001 CrossRefGoogle Scholar
  25. 25.
    Kim YC, Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Investig 125:25–32.  https://doi.org/10.1172/JCI73939 CrossRefGoogle Scholar
  26. 26.
    Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023.  https://doi.org/10.1038/ncb2329 CrossRefGoogle Scholar
  27. 27.
    Thorburn A, Thamm DH, Gustafson DL (2014) Autophagy and cancer therapy. Mol Pharmacol 85:830–838.  https://doi.org/10.1124/mol.114.091850 CrossRefGoogle Scholar
  28. 28.
    Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, Hoppe G, Bianchi ME, Tracey KJ, Zeh HJ, Lotze MT (2010) Endogenous HMGB1 regulates autophagy. J Cell Biol 190:881–892.  https://doi.org/10.1083/jcb.200911078 CrossRefGoogle Scholar
  29. 29.
    Tang D, Kang R, Coyne CB, Zeh HJ, Lotze MT (2012) PAMPs and DAMPs: signal 0 s that spur autophagy and immunity. Immunol Rev 249:158–175.  https://doi.org/10.1111/j.1600-065X.2012.01146.x CrossRefGoogle Scholar
  30. 30.
    Tang D, Kang R, Livesey KM, Zeh HJ, Lotze MT (2011) High mobility group box 1 (HMGB1) activates an autophagic response to oxidative stress. Antioxid Redox Signal 15:2185–2195.  https://doi.org/10.1089/ars.2010.3666 CrossRefGoogle Scholar
  31. 31.
    Parker K, Sinha P, Horn L, Clements V, Ostrand-Rosenberg S (2014) HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells. Cancer Res 74:5723–5733CrossRefGoogle Scholar
  32. 32.
    Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99:7610–7615.  https://doi.org/10.1073/pnas.112203099 CrossRefGoogle Scholar
  33. 33.
    Khor TO, Huang MT, Prawan A, Liu Y, Hao X, Yu S, Cheung WK, Chan JY, Reddy BS, Yang CS, Kong AN (2008) Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila) 1:187–191.  https://doi.org/10.1158/1940-6207.CAPR-08-0028 CrossRefGoogle Scholar
  34. 34.
    Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, Conney AH, Kong AN (2006) Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res 66:8293–8296.  https://doi.org/10.1158/0008-5472.CAN-06-0300 CrossRefGoogle Scholar
  35. 35.
    Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S (2008) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA 105:13568–13573.  https://doi.org/10.1073/pnas.0806268105 CrossRefGoogle Scholar
  36. 36.
    Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S (2008) RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res 68:7975–7984.  https://doi.org/10.1158/0008-5472.CAN-08-1401 CrossRefGoogle Scholar
  37. 37.
    Beury DW, Carter KA, Nelson C, Sinha P, Hanson E, Nyandjo M, Fitzgerald PJ, Majeed A, Wali N, Ostrand-Rosenberg S (2016) Myeloid-derived suppressor cell survival and function are regulated by the transcription factor Nrf2. J Immunol 196:3470–3478.  https://doi.org/10.4049/jimmunol.1501785 CrossRefGoogle Scholar
  38. 38.
    Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL (1999) Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274:26071–26078.  https://doi.org/10.1074/jbc.274.37.26071 CrossRefGoogle Scholar
  39. 39.
    Wild AC, Moinova HR, Mulcahy RT (1999) Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274:33627–33636.  https://doi.org/10.1074/jbc.274.47.33627 CrossRefGoogle Scholar
  40. 40.
    Zhu H, Itoh K, Yamamoto M, Zweier JL, Li Y (2005) Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett 579:3029–3036.  https://doi.org/10.1016/j.febslet.2005.04.058 CrossRefGoogle Scholar
  41. 41.
    Li J, Johnson D, Calkins M, Wright L, Svendsen C, Johnson J (2005) Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 83:313–328.  https://doi.org/10.1093/toxsci/kfi027 CrossRefGoogle Scholar
  42. 42.
    Parker KH, Horn LA, Ostrand-Rosenberg S (2016) High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol 100:463–470.  https://doi.org/10.1189/jlb.3HI0715-305R CrossRefGoogle Scholar
  43. 43.
    Dodson M, Redmann M, Rajasekaran NS, Darley-Usmar V, Zhang J (2015) Correction: KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 471:431.  https://doi.org/10.1042/BJ4710431 CrossRefGoogle Scholar
  44. 44.
    Dodson M, Redmann M, Rajasekaran NS, Darley-Usmar V, Zhang J (2015) KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 469:347–355.  https://doi.org/10.1042/BJ20150568 CrossRefGoogle Scholar
  45. 45.
    Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, Kong AN (2008) Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol 76:1485–1489.  https://doi.org/10.1016/j.bcp.2008.07.017 CrossRefGoogle Scholar
  46. 46.
    Briceno E, Reyes S, Sotelo J (2003) Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg Focus 14:e3CrossRefGoogle Scholar
  47. 47.
    Su Z, Wang T, Zhu H, Zhang P, Han R, Liu Y, Ni P, Shen H, Xu W, Xu H (2015) HMGB1 modulates Lewis cell autophagy and promotes cell survival via RAGE-HMGB1-Erk1/2 positive feedback during nutrient depletion. Immunobiology 220:539–544.  https://doi.org/10.1016/j.imbio.2014.12.009 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of Maryland Baltimore County (UMBC)BaltimoreUSA
  2. 2.Department of PathologyUniversity of UtahSalt Lake CityUSA
  3. 3.Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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