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Biology of Myeloid-Derived Suppressor Cells

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Oncoimmunology

Abstract

The accumulation of highly immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs) is one of the immunological hallmarks of cancer. MDSCs are a heterogeneous population of bone marrow-derived immature myeloid cells that accumulate in the blood, peripheral lymphoid organs, and tumor tissues, which correlates with a poor clinical outcome in cancer patients. The main feature of MDSCs is their ability to suppress antitumor responses leading to tumor progression. Thus, MDSCs represent an attractive therapeutic target to enhance antitumor responses in cancer.

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References

  1. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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  PubMed  Google Scholar 

  3. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin LC. Expansion of myeloid immune suppressor gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;4:409–21.

    Article  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Haile LA, Greten TF, Korangy F. Immune suppression: the hallmark of myeloid-derived suppressor cells. Immunol Investig. 2012;41:581–94.

    Article  CAS  Google Scholar 

  6. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13:739–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C, Geilich M, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2010;40:22–35.

    Article  CAS  PubMed  Google Scholar 

  8. Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181:5791–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37:208–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7(1):10.

    Google Scholar 

  11. 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;61:1155–67.

    Article  CAS  PubMed  Google Scholar 

  12. Condamine T, Dominguez G, Youn J, Kossenkov A, Mony S, Alicea-Torres K, et al. Lectin-type oxidized LDL receptor 1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol. 2016;1:1–15.

    Article  Google Scholar 

  13. Li H, Han Y, Guo Q, Zhang M, Cao X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J Immunol. 2009;182(1):240–9.

    Article  CAS  PubMed  Google Scholar 

  14. Elkabets M, Ribeiro VS, Dinarello CA, Ostrand-Rosenberg S, Di Santo JP, Apte RN, et al. IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur J Immunol. 2010;40(12):3347–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li Y, Tu Z, Qian S, Fung JJ, Markowitz SD, Kusner LL, et al. Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis. J Immunol. 2014;193:2127–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med. 2005;202(7):931–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kusmartsev S, Gabrilobivch DI. STAT1 signaling regulates tumor-associated macrophages-mediated T cell deletion. J Immunol. 2005;174(8):4880–91.

    Article  CAS  PubMed  Google Scholar 

  18. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007;13(7):828–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lu T, Ramakrishmanm R, Altiok S, Youn JL, Cheng P, Celis E, et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest. 2011;121:4015–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med. 2011;208:1949–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, et al. Mechanism regulating reactive oxygen species in tumor induced myeloid-derived suppressor cells. J Immunol. 2009;182(9):5693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, et al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med. 2003;198:1741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179(2):977–83.

    Article  CAS  PubMed  Google Scholar 

  24. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, et al. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol. 2013;190(7):3783–97.

    Article  CAS  PubMed  Google Scholar 

  25. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T cell activation by depleting Cystine and cysteine. Cancer Res. 2010;70(1):68–77.

    Article  CAS  PubMed  Google Scholar 

  26. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 2006;66(2):1123–31.

    Article  CAS  PubMed  Google Scholar 

  27. Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, et al. Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res. 2010;70(1):99–108.

    Article  CAS  PubMed  Google Scholar 

  28. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111:4233–44.

    Article  CAS  PubMed  Google Scholar 

  30. Linday D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunol. 2013;138(2):105–15.

    Article  CAS  Google Scholar 

  31. Haverkamp JM, Crist SA, Elzey BD, Cimen C, Ratliff TL. In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol. 2011;41(3):749–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maenhout SK, Van-Lint S, Emeagi PU, Thielemans K, Aerts JL. Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral counterparts. Int J Cancer. 2014;134:1077–90.

    Article  CAS  PubMed  Google Scholar 

  33. Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunol. 2014;143(4):512–9.

    Article  CAS  Google Scholar 

  34. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011;32(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  35. Lechner MG, Liebertz DJ, Epstein AL. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol. 2010;185:2273–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol. 2015;98(6):913–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207(11):2439–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCraffey JC, et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity. 2016;44(2):303–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mattei F, Schiavoni G, Sestili P, Spadaro F, Fragale A, Sistigu A, et al. IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment. Neoplasia. 2012;14:1223–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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;123:4464–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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  PubMed  Google Scholar 

  42. Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol. 2013;14:211–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A. 2015;112:566–75.

    Article  CAS  Google Scholar 

  44. Cheng P, Kumar V, Liu H, Youn JI, Fishman M, Sherman S, et al. Effects of notch signaling on regulation of myeloid cell differentiation in cancer. Cancer Res. 2014;74:141–52.

    Article  CAS  PubMed  Google Scholar 

  45. Wang SH, Lu QY, Guo YH, Song YY, Liu PJ, Wang YC. The blockage of notch signalling promoted the generation of polymorphonuclear myeloid-derived suppressor cells with lower immunosuppression. Eur J Cancer. 2016;68:90–105.

    Article  CAS  PubMed  Google Scholar 

  46. Antonioli L, Blandizzi C, Pacher P, Haskó G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer. 2013;13:842–57.

    Article  CAS  PubMed  Google Scholar 

  47. Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, et al. Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J Immunol. 2011;187:6120–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia. 2013;15:1400–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Van Deventer HW, Burgents JE, Wu QP, Woodford RM, Brickey WJ, Allen IC, et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 2010;70:10161–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Hong EH, Chang SY, Lee BR, Kim YS, Lee JM, Kang CY, et al. Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells. Int J Cancer. 2013;132:2839–48.

    Article  CAS  PubMed  Google Scholar 

  51. Yang Y, Zhang R, Xia F, Zou T, Huang A, Xiong S, et al. LPS converts gr-1(+)CD115(+) myeloid-derived suppressor cells from M2 to M1 via P38 MAPK. Exp Cell Res. 2013;319:1774–83.

    Article  CAS  PubMed  Google Scholar 

  52. Diao J, Yang X, Song X, Chen S, He Y, Wang Q, et al. Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med Oncol. 2015;32(35):1–10.

    CAS  Google Scholar 

  53. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 2008;14:408–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bunt SK, Clements VK, Hanson EM, Sinha P, Ostrand-Rosenberg S. Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through toll-like receptor 4. J Leukoc Biol. 2009;85:996–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M. Tumor necrosis factor-α blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity. 2013;38:541–54.

    Article  CAS  PubMed  Google Scholar 

  56. Hu X, Li B, Li X, Zhao X, Wan L, Lin G, et al. Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J Immunol. 2014;192:1320–31.

    Article  CAS  PubMed  Google Scholar 

  57. Polz J, Remke A, Weber S, Schmidt D, Weber-Steffens D, Pietryga-Krieger A, et al. Myeloid suppressor cells require membrane TNFR2 expression for suppressive activity. Immun Inflamm Dis. 2014;2(2):121–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao X, Rong L, Zhao X, Li X, Liu X, Deng J, et al. TNF signaling drives myeloid-derived suppressor cell accumulation. J Clin Invest. 2012;122:4094–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest. 2006;116:2777–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sinha P, Parker KH, Horn L, Ostrand-Rosenberg S. Tumor-induced myeloid-derived suppressor cell function is independent of IFN-γ and IL-4Rα. Eur J Immunol. 2012;42:2052–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schouppe E, Mommer C, Movahedi K, Laoui D, Morias Y, Gysemans C, et al. Tumor-induced myeloid-derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8+ T-cell activation events. Eur J Immunol. 2013;43:2930–42.

    Article  CAS  PubMed  Google Scholar 

  62. Medina-Echeverz J, Haile LA, Zhao F, Gamrekelashvili J, Ma C, Métais JY, et al. IFN-γ regulates survival and function of tumor-induced CD11b+ gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. Eur J Immunol. 2014;44:2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol. 2003;170:270–8.

    Article  CAS  PubMed  Google Scholar 

  64. Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 2005;65:11743–51.

    Article  CAS  PubMed  Google Scholar 

  65. Roth F, De La Fuente AC, Vella JL, Zoso A, Inverardi L, Serafini P. Aptamer-mediated blockade of IL4Rα triggers apoptosis of MDSCs and limits tumor progression. Cancer Res. 2012;72:1373–83.

    Article  CAS  PubMed  Google Scholar 

  66. Donkor MK, Lahue E, Hoke TA, Shafer LR, Coskun U, Solheim JC, et al. Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int Immunopharmacol. 2009;9:937–48.

    Article  CAS  PubMed  Google Scholar 

  67. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118:5498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Obermajer N, Kalinski P. Generation of myeloid-derived suppressor cells using prostaglandin E2. Transplantation Res. 2012;1(15):1–6.

    Google Scholar 

  69. Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, et al. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer. 2010;10(464):1–13.

    Google Scholar 

  70. Fujita M, Kohanbash G, Fellows-Mayle W, Hamilton RL, Komohara Y, Decker SA, et al. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res. 2011;71:2664–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mao Y, Poschke I, Wennerberg E, Pico de Coaña Y, Egyhazi Brage S, Schultz I, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 2013;73:3877–87.

    Article  CAS  PubMed  Google Scholar 

  72. Obermajer N, Wong JL, Edwards RP, Odunsi K, Moysich K, Kalinski P. PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol Investig. 2012;41:635–57.

    Article  CAS  Google Scholar 

  73. Parker KH, Sinha P, Horn LA, Clements VK, Yang H, Li J, et al. HMGB1 enhances immune suppression by facilitating the differentiation and suppressive activity of myeloid-derived suppressor cells. Cancer Res. 2014;74(20):5723–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Parker KH, Horn LA, Ostrand-Rosenber S. High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol. 2016;100(3):463–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Su Z, Ni P, She P, Liu Y, Richard SA, Xu W, et al. Bio-HMGB1 from breast cancer contributes to M-MDSC differentiation from bone marrow progenitor cells and facilitates conversion of monocytes into MDSC-like cells. Cancer Immunol Immunother. 2017;66:391–401.

    Article  CAS  PubMed  Google Scholar 

  76. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mahadevan NR, Zanetti M. Tumor stress inside out: cell-extrinsic effects of the unfolded protein response in tumor cells modulate the immunological landscape of the tumor microenvironment. J Immunol. 2011;187(9):4403–9.

    Article  CAS  PubMed  Google Scholar 

  78. Bettigole SE, Glimcher LH. Endoplasmic reticulum stress in immunity. Annu Rev Immunol. 2015;33:107–38.

    Article  CAS  PubMed  Google Scholar 

  79. Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014;124(6):2626–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee BR, Chang SY, Hong EH, Kwon BE, Kim HM, Kim YJ, et al. Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells. Oncotarget. 2014;5(23):12331–45.

    Article  PubMed  PubMed Central  Google Scholar 

  81. 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(3):389–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cubillos JR, Mohamed E, Rodriguez PC. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J ImmunoTher Cancer. 2017;5(5):1–10.

    Google Scholar 

  83. Condamine T, Gabrilovich DI. Can the suppressive activity of myeloid-derived suppressor cells be “chop”ped? Immunity. 2014;41(3):341–2.

    Article  CAS  PubMed  Google Scholar 

  84. Choksawangkarn W, Graham LM, Burke M, Lee SB, Ostrand-Rosenberg S, Fenselau C, et al. Peptide-based systems analysis of inflammation induced myeloid-derived suppressor cells reveals diverse signaling pathways. Proteomics. 2016;16:1881–8.

    Article  CAS  PubMed  Google Scholar 

  85. Gato M, Blanco-Luquin I, Zudaire M, de Morentin XM, Perez-Valderrama E, Zabaleta A, et al. Drafting the proteome landscape of myeloid-derived suppressor cells. Proteomics. 2016;16:367–78.

    Article  CAS  PubMed  Google Scholar 

  86. Chornoguz O, Grmai L, Sinha P, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S. Proteomic pathway analysis reveals inflammation increases myeloid-derived suppressor cell resistance to apoptosis. Mol Cell Proteomics. 2011;10:1–9.

    Article  CAS  Google Scholar 

  87. Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V, et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. 2012;7(2):1–13.

    Article  CAS  Google Scholar 

  88. Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol. 2012;91(1):167–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125(9):3365–76.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, et al. RORC1 regulates tumor-promoting “emergency” Granulo-Monocytopoiesis. Cancer Cell. 2015;28:253–69.

    Article  CAS  PubMed  Google Scholar 

  91. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.

    Article  CAS  PubMed  Google Scholar 

  92. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016;16:431–46.

    Article  CAS  PubMed  Google Scholar 

  93. Fridlender Z, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: n1 versus N2 TAN. Cancer Cell. 2009;16:183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Andzinski L, Kasnitz N, Stahnke S, Wu CF, Gereke M, von Köckritz-Blickwede M, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer. 2016;138:1982–93.

    Article  CAS  PubMed  Google Scholar 

  95. Moses K, Brandau S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol. 2016;28:187–96.

    Article  CAS  PubMed  Google Scholar 

  96. Cimen Bozkus C, Elzey BD, Crist SA, Ellies LG, Ratliff TL. Expression of cationic amino acid transporter 2 is required for myeloid-derived suppressor cell-mediated control of T cell immunity. J Immunol. 2015;195:5237–50.

    Article  CAS  PubMed  Google Scholar 

  97. Mairhofer DG, Ortner D, Tripp CH, Schaffenrath S, Fleming V, Heger L, et al. Impaired gp100-specific CD8(+) T-cell responses in the presence of myeloid-derived suppressor cells in a spontaneous mouse melanoma model. J Invest Dermatol. 2015;135:2785–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, Stephen TL, Ranganathan A, Deshpande C, et al. tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. 2014;124(12):5466–80.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ortiz M, Lu L, Ramachandran I, Gabrilovich D. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res. 2014;2:50–8.

    Article  CAS  PubMed  Google Scholar 

  100. 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;11:1–11.

    Google Scholar 

  101. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol. 2011;11(7):856–61.

    Article  CAS  PubMed  Google Scholar 

  102. Vetsika EK, Koinins F, Gioulbasani M, Aggouraki D, Koutoulaki A, Skalidaki E, et al. A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. J Immunol Res. 2014;2014:1–12.

    Article  CAS  Google Scholar 

  103. Ramachandran IR, Condamine T, Lin C, Herlihy SE, Garfall A, Vogl DT, et al. Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. Cancer Lett. 2016;371:117–24.

    Article  CAS  PubMed  Google Scholar 

  104. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014;63:247–57.

    Article  CAS  PubMed  Google Scholar 

  105. Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant Ipilimumab. PLoS One. 2014;9(2):1–9.

    Article  CAS  Google Scholar 

  106. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6(237):1–13.

    Article  CAS  Google Scholar 

  107. Weber J, Gibney G, Kudchadkar R, Yu B, Cheng P, Martinez AJ, et al. Phase I/II study of metastatic melanoma patients treated with Nivolumab who had progressed after Ipilimumab. Cancer Immunol Res. 2016;4(4):345–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356–64.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, et al. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Rep. 2012;2(3):628–39.

    Article  CAS  PubMed  Google Scholar 

  110. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11:6713–21.

    Article  CAS  PubMed  Google Scholar 

  111. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5- fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70:3052–61.

    Article  CAS  PubMed  Google Scholar 

  112. Naiditch H, Shurin MR, Shurin GV. Targeting myeloid regulatory cells in cancer by chemotherapeutic agents. Immunol Res. 2011;50(2–3):276–85.

    Article  CAS  PubMed  Google Scholar 

  113. Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T cell transfer in breast cancer. Cancer Res. 2014;74(1):104–18.

    Article  CAS  PubMed  Google Scholar 

  114. Dominguez G, Condamine T, Mony S, Hashimoto A, Wang F, Liu Q, et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res. 2016;23:2942–50.

    Article  PubMed  CAS  Google Scholar 

  115. Qin H, Lerman B, Sakamaki I, Wei G, Cha S, Rao SS, et al. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med. 2014;20(6):676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010;16(6):1812–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Beury DW, Carter KA, Nelson C, Sinha P, Hanson E, Nyandjo M, et al. Myeloid-derived suppressor cell survival and function are regulated by the transcription factor Nrf2. J Immunol. 2016;196(8):3470–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hirano K, Hosoi A, Matsushita H, Iino T, Ueha S, Matsushima K, et al. The nitric oxide radical scavenger carboxy-PTIO reduces the immunosuppressive activity of myeloid-derived suppressor cells and potentiates the antitumor activity of adoptive cytotoxic T lymphocyte immunotherapy. OncoImmunol. 2015;4(8):1–12.

    Article  CAS  Google Scholar 

  119. Rodriguez PC, Quiceno D, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64:5839–49.

    Article  CAS  PubMed  Google Scholar 

  120. Noonan KA, Ghosh N, Rudraraju L, Bui M, Borrello I. Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma. Cancer Immunol Res. 2014;2:725–31.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006;203(12):2691–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Califano JA, Khan Z, Noonan KA, Rudraraju L, Zhang Z, Wang H, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21:30–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21:39–48.

    Article  CAS  PubMed  Google Scholar 

  124. De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, Del Soldato P, et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A. 2005;102:4185–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007;67:4507–13.

    Article  CAS  PubMed  Google Scholar 

  126. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–66.

    CAS  PubMed  Google Scholar 

  127. Kusmartsev S, Gabrilovich DI. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J Leukoc Biol. 2003;74(2):186–96.

    Article  CAS  PubMed  Google Scholar 

  128. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.

    Article  CAS  PubMed  Google Scholar 

  129. Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, Lush R, et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 2003;63(15):4441–9.

    CAS  PubMed  Google Scholar 

  130. Mirza N, Fishman M, Ficke I, Dunn M, Neuger AM, Frost TJ, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66:9299–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007;67(22):11021–8.

    Article  CAS  PubMed  Google Scholar 

  132. Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich DI. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother. 2014;62(5):909–18.

    Article  CAS  Google Scholar 

  133. Long AH, Highfill SL, Cui Y, Smith JP, Walker AJ, Ramakrishna S, et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res. 2016;4(10):869–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Alicea-Torres, K., Gabrilovich, D.I. (2018). Biology of Myeloid-Derived Suppressor Cells. In: Zitvogel, L., Kroemer, G. (eds) Oncoimmunology. Springer, Cham. https://doi.org/10.1007/978-3-319-62431-0_10

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