Tumor Biology

, Volume 36, Issue 5, pp 3159–3169 | Cite as

Highlights on mechanisms of drugs targeting MDSCs: providing a novel perspective on cancer treatment

  • Wei Pan
  • Qian Sun
  • Yang Wang
  • Jian Wang
  • Shui Cao
  • Xiubao Ren


The hallmark of tumor microenvironment is that it makes up of numerous immunomodulatory cells and factors which exert essential roles in immunoprotection and immunosuppression in addition to tumor cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells reported to promote immunosuppression and angiogenesis and facilitate tumor metastasis and invasion. The wide scope of MDSCs functional activities make these cells promising targets for effective cancer treatments. In this review, we briefly discuss the origin, subpopulation, and functions of MDSCs, as well as the potential to target these cells for therapeutic benefit. We focus on the underlying molecular mechanisms of these drugs targeting MDSCs, mainly from the standpoint of molecules related to drug targets.


MDSCs Mechanisms Tumor microenvironment Subpopulation Functional regulation Therapeutic implication 



Myeloid-derived suppressor cells


Natural killer


Dendritic cells


Cytotoxic T lymphocytes


Regulatory T lymphocytes


Matrix metallo proteinase


Monocyte chemoattractant protein 1


Vascular endothelial growth factor


inducible NO synthase


Phosphodiesterase 5


High mobility group box 1


Transforming growth factor β


CCAAT/enhancer-binding protein β


Interferon regulatory factor


Nuclear factor κB


Janus kinase


Signal transducer and activator of transcription


Indoleamine 2,3-dioxygenase


Granulocyte colony-stimulating factor


Cyclooxygenase 2


Bone morphogenetic protein 4


Activated T cells (ATCs) armed with bispecific antibodies


The toll-like receptor (TLR) 9 ligand



This work was supported by the National Natural Science Foundation of China (No. 81472471). John E. Anderson, M.D. from Johns Hopkins University provided his personal assistance in the preparation of the work.

Conflicts of interest



  1. 1.
    Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007;67:425–6.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bronte V. Myeloid-derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol. 2009;39:2670–2.CrossRefPubMedGoogle Scholar
  3. 3.
    Ochando JC, Chen SH. Myeloid-derived suppressor cells in transplantation and cancer. Immunol Res. 2012;54:275–85.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Brandau S, Moses K, Lang S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: Cousins, siblings or twins? Semin Cancer Biol. 2013;23:171–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A. 2007;104:20262–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mucha J, Majchrzak K, Taciak B, Hellmen E, Krol M. MDSCs mediate angiogenesis and predispose canine mammary tumor cells for metastasis via IL-28/IL-28RA (IFN-lambda) signaling. PLoS One. 2014;9:e103249.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Youn JI, Gabrilovich DI. The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010;40:2969–75.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhong H, Gutkin DW, Han B, Ma Y, Keskinov AA, Shurin MR, et al. Origin and pharmacological modulation of tumor-associated regulatory dendritic cells. Int J Cancer. 2014;134:2633–45.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 2012;61:255–63.CrossRefPubMedGoogle Scholar
  10. 10.
    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;22:238–44.CrossRefPubMedGoogle Scholar
  11. 11.
    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;91:167–81.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008;181:5791–802.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ribechini E, Greifenberg V, Sandwick S, Lutz MB. Subsets, expansion and activation of myeloid-derived suppressor cells. Med Microbiol Immunol. 2010;199:273–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Fujimura T, Mahnke K, Enk AH. Myeloid derived suppressor cells and their role in tolerance induction in cancer. J Dermatol Sci. 2010;59:1–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, et al. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007;25:2546–53.CrossRefPubMedGoogle Scholar
  17. 17.
    Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, et al. IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol. 2009;182:6562–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Srivastava MK, Bosch JJ, Thompson JA, Ksander BR, Edelman MJ, Ostrand-Rosenberg S. Lung cancer patients' CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2008;57:1493–504.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69:1553–60.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49–59.CrossRefPubMedGoogle Scholar
  21. 21.
    Dolcetti L, Marigo I, Mantelli B, Peranzoni E, Zanovello P, Bronte V. Myeloid-derived suppressor cell role in tumor-related inflammation. Cancer Lett. 2008;267:216–25.CrossRefPubMedGoogle Scholar
  22. 22.
    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;74:5723–33.Google Scholar
  23. 23.
    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cohen PA, Ko JS, Storkus WJ, Spencer CD, Bradley JM, Gorman JE, et al. Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Invest. 2012;41:680–710.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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;66:1123–31.Google Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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;43:2930–294.CrossRefPubMedGoogle Scholar
  29. 29.
    Hibi S, Lohler J, Friel J, Stocking C, Ostertag W. Induction of monocytic differentiation and tumorigenicity by v-ha-ras in differentiation arrested hematopoietic cells. Blood. 1993;81:1841–8.PubMedGoogle Scholar
  30. 30.
    Behre G, Singh SM, Liu H, Bortolin LT, Christopeit M, Radomska HS, et al. Ras signaling enhances the activity of c/ebp alpha to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem. 2002;277:26293–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. STAT3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008;118:3367–77.Google Scholar
  32. 32.
    Guedez L, Jensen-Taubman S, Bourboulia D, Kwityn CJ, Wei B, Caterina J, et al. TIMP-2 targets tumor-associated myeloid suppressor cells with effects in cancer immune dysfunction and angiogenesis. J Immunother. 2012;35:502–12.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Boelte KC, Gordy LE, Joyce S, Thompson MA, Yang L, Lin PC. Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS One. 2011;6:e18534.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450:825–31.CrossRefPubMedGoogle Scholar
  35. 35.
    Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 2011;9:e1001162.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13:23–35.Google Scholar
  37. 37.
    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;9:133–48.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bierie B, Moses HL. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev. 2010;21:49–59.CrossRefPubMedGoogle Scholar
  39. 39.
    Stover DG, Bierie B, Moses HL. A delicate balance: TGF-beta and the tumor microenvironment. J Cell Biochem. 2007;101:851–61.Google Scholar
  40. 40.
    Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G, et al. Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol. 2012;188:5365–76.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Gorgens A, et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer. 2013;133:1653–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Dugo M, Nicolini G, Tragni G, Bersani I, Tomassetti A, Colonna V, Del Vecchio M, De Braud F, Canevari S, Anichini A, Sensi M: A melanoma subtype with intrinsic resistance to braf inhibition identified by receptor tyrosine kinases gene-driven classification. Oncotarget 2015.Google Scholar
  43. 43.
    Liu L, Ye TH, Han YP, Song H, Zhang YK, Xia Y, et al. Reductions in Myeloid-Derived suppressor cells and lung metastases using AZD4547 treatment of a metastatic murine breast tumor model. Cell Physiol Biochem. 2014;33:633–45.CrossRefPubMedGoogle Scholar
  44. 44.
    Espagnolle N, Barron P, Mandron M, Blanc I, Bonnin J, Agnel M, et al. Specific inhibition of the VEGFR-3 tyrosine kinase by SAR131675 reduces peripheral and tumor associated immunosuppressive myeloid cells. Cancers (Basel). 2014;6:472–90.CrossRefGoogle Scholar
  45. 45.
    Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69:2514–22.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of STAT3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69:2506–13.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Conway JG, McDonald B, Parham J, Keith B, Rusnak DW, Shaw E, et al. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cfms kinase inhibitor GW2580. Proc Natl Acad Sci U S A. 2005;102:16078–83.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Morello S, Miele L. Targeting the adenosine A2b receptor in the tumor microenvironment overcomes local immunosuppression by myeloid-derived suppressor cells. Oncoimmunology. 2014;3:e27989.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res. 2007;67:11438–46.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Shen L, Sundstedt A, Ciesielski M, Miles KM, Celander M, Adelaiye R, et al. Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol Res. 2015;3:136–48.CrossRefPubMedGoogle Scholar
  52. 52.
    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.Google Scholar
  53. 53.
    Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci U S A. 2011;108:17111–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hu X, Bardhan K, Paschall AV, Yang D, Waller JL, Park MA, et al. Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. J Biol Chem. 2013;288:19103–15.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013;73:3007–18.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Zhang M, Liu Q, Mi S, Liang X, Zhang Z, Su X, et al. Both mir-17-5p and mir-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J Immunol. 2011;186:4716–24.CrossRefPubMedGoogle Scholar
  57. 57.
    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.Google Scholar
  58. 58.
    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.CrossRefPubMedGoogle Scholar
  59. 59.
    Mace TA, King SA, Ameen Z, Elnaggar O, Young G, Riedl KM, Schwartz SJ, Clinton SK, Knobloch TJ, Weghorst CM, Lesinski GB: Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling. Cancer Immunol Immunother 2014Google Scholar
  60. 60.
    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;202:931–9.Google Scholar
  61. 61.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    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.CrossRefPubMedGoogle Scholar
  63. 63.
    Cao Y, Slaney CY, Bidwell BN, Parker BS, Johnstone CN, Rautela J, et al. BMP4 inhibits breast cancer metastasis by blocking myeloid-derived suppressor cell activity. Cancer Res. 2014;74:5091–102.CrossRefPubMedGoogle Scholar
  64. 64.
    Michels T, Shurin GV, Naiditch H, Sevko A, Umansky V, Shurin MR. Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner. J Immunotoxicol. 2012;9:292–300.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lee YH, Lee YR, Park CS, Im SA, Song S, Hong JT, et al. Baccatin III, a precursor for the semisynthesis of paclitaxel, inhibits the accumulation and suppressive activity of myeloid-derived suppressor cells in tumor-bearing mice. Int Immunopharmacol. 2014;21:487–93.CrossRefPubMedGoogle Scholar
  66. 66.
    Zhang C, Li B, Zhang X, Hazarika P, Aggarwal BB, Duvic M. Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients' PBMCs: Potential role for STAT-3 and NF-κB signaling. J Invest Dermatol. 2010;130:2110–9.Google Scholar
  67. 67.
    Weissenberger J, Priester M, Bernreuther C, Rakel S, Glatzel M, Seifert V, et al. Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res. 2010;16:5781–95.CrossRefPubMedGoogle Scholar
  68. 68.
    Clark CA, McEachern MD, Shah SH, Rong Y, Rong X, Smelley CL, et al. Curcumin inhibits carcinogen and nicotine-induced Mammalian target of rapamycin pathway activation in head and neck squamous cell carcinoma. Cancer Prev Res (Phila). 2010;3:1586–95.CrossRefGoogle Scholar
  69. 69.
    Tu SP, Jin H, Shi JD, Zhu LM, Suo Y, Lu G, et al. Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev Res (Phila). 2012;5:205–15.CrossRefGoogle Scholar
  70. 70.
    Lawson JA, Adams WJ, Morris DL. Ranitidine and cimetidine differ in their in vitro and in vivo effects on human colonic cancer growth. Br J Cancer. 1996;73:872–6.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Natori T, Sata M, Nagai R, Makuuchi M. Cimetidine inhibits angiogenesis and suppresses tumor growth. Biomed Pharmacother. 2005;59:56–60.CrossRefPubMedGoogle Scholar
  72. 72.
    Adams WJ, Morris DL, Ross WB, Lubowski DZ, King DW, Peters L. Cimetidine preserves non-specific immune function after colonic resection for cancer. Aust N Z J Surg. 1994;64:847–52.CrossRefPubMedGoogle Scholar
  73. 73.
    Takahashi HK, Watanabe T, Yokoyama A, Iwagaki H, Yoshino T, Tanaka N, et al. Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. Mol Pharmacol. 2006;70:450–3.CrossRefPubMedGoogle Scholar
  74. 74.
    Kubota T, Fujiwara H, Ueda Y, Itoh T, Yamashita T, Yoshimura T, et al. Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients. Br J Cancer. 2002;86:1257–61.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Thakur A, Schalk D, Sarkar SH, Al-Khadimi Z, Sarkar FH, Lum LG. A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2012;61:497–509.CrossRefPubMedGoogle Scholar
  76. 76.
    Thakur A, Schalk D, Tomaszewski E, Kondadasula SV, Yano H, Sarkar FH, et al. Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE2 dependent pathway. J Transl Med. 2013;11:35.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zoglmeier C, Bauer H, Norenberg D, Wedekind G, Bittner P, Sandholzer N, et al. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res. 2011;17:1765–75.CrossRefPubMedGoogle Scholar
  78. 78.
    Chakraborty P, Das S, Banerjee K, Sinha A, Roy S, Chatterjee M, et al. A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response. Immunopharmacol Immunotoxicol. 2014;36:165–75.CrossRefPubMedGoogle Scholar
  79. 79.
    Lee JM, Seo JH, Kim YJ, Kim YS, Ko HJ, Kang CY. The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment. Int J Cancer. 2012;131:741–51.CrossRefPubMedGoogle Scholar
  80. 80.
    Hasnis E, Alishekevitz D, Gingis-Veltski S, Bril R, Fremder E, Voloshin T, Raviv Z, Karban A, Shaked Y: Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia 2014Google Scholar
  81. 81.
    Seago ND, Clark DA, Miller MJ. Role of inducible nitric oxide synthase (iNOS) and peroxynitrite in gut inflammation. Inflamm Res. 1995;44 Suppl 2:S153–4.CrossRefPubMedGoogle Scholar
  82. 82.
    Baek MJ. Does braf mutation and extracellular signal regulated kinase expression in patients with colorectal cancer have any prognostic significance? Ann Coloproctol. 2015;31:1–2.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346–58.CrossRefPubMedGoogle Scholar
  84. 84.
    Sorrentino R, Pinto A, Morello S. The adenosinergic system in cancer: Key therapeutic target. Oncoimmunology. 2013;2:e22448.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Metsola J, Maksimow M, Ojaniemi M, Metsola H, Marttila-Ichihara F, Vuolteenaho R, Yegutkin GG, Salmi M, Hallman M, Jalkanen S: Postnatal development and LPS-responsiveness of pulmonary adenosine receptor expression and of adenosine-metabolizing enzymes in mice. Pediatr Res 2014.Google Scholar
  86. 86.
    Bianchi G, Vuerich M, Pellegatti P, Marimpietri D, Emionite L, Marigo I, et al. ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment. Cell Death Dis. 2014;5:e1135.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Roskoski Jr R. Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007;356:323–8.Google Scholar
  88. 88.
    George S. Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep. 2007;9:323–7.CrossRefPubMedGoogle Scholar
  89. 89.
    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;203:2691–702.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Hartman ZC, Osada T, Glass O, Yang XY, Lei GJ, Lyerly HK, et al. Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity. Cancer Res. 2010;70:7209–20.Google Scholar
  91. 91.
    Despars G, O'Neill HC. A role for niches in the development of a multiplicity of dendritic cell subsets. Exp Hematol. 2004;32:235–43.CrossRefPubMedGoogle Scholar
  92. 92.
    Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S. Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood. 2011;117:5381–90.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Liu Q, Tan Q, Zheng Y, Chen K, Qian C, Li N, Wang Q, Cao X: Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation. J Biol Chem 2014Google Scholar
  94. 94.
    Wajant H, Pfizenmaier K, Scheurich P. Non-apoptotic Fas signaling. Cytokine Growth Factor Rev. 2003;14:53–66.CrossRefPubMedGoogle Scholar
  95. 95.
    Zhang Y, Liu Q, Zhang M, Yu Y, Liu X, Cao X. Fas signal promotes lung cancer growth by recruiting myeloid-derived suppressor cells via cancer cell-derived PGE2. J Immunol. 2009;182:3801–8.CrossRefPubMedGoogle Scholar
  96. 96.
    Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, et al. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol. 2012;188:5954–61.CrossRefPubMedGoogle Scholar
  97. 97.
    Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, et al. CD95 promotes tumour growth. Nature. 2010;465:492–6.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    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.Google Scholar
  99. 99.
    Obermajer N, Kalinski P. Generation of myeloid-derived suppressor cells using prostaglandin E2. Transplant Res. 2012;1:15.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Ketolainen JM, Alarmo EL, Tuominen VJ, Kallioniemi A. Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4. Breast Cancer Res Treat. 2010;124:377–86.CrossRefPubMedGoogle Scholar
  101. 101.
    Guo X, Wang XF. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 2009;19:71–88.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Waight JD, Hu Q, Miller A, Liu S, Abrams SI. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One. 2011;6:e27690.Google Scholar
  103. 103.
    Luyckx A, Schouppe E, Rutgeerts O, Lenaerts C, Fevery S, Devos T, et al. G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells. Clin Immunol. 2012;143:83–7.Google Scholar
  104. 104.
    Jagetia GC, Aggarwal BB. "Spicing up" of the immune system by curcumin. J Clin Immunol. 2007;27:19–35.CrossRefPubMedGoogle Scholar
  105. 105.
    Freston JW. Cimetidine. I. Developments, pharmacology, and efficacy. Ann Intern Med. 1982;97:573–80.CrossRefPubMedGoogle Scholar
  106. 106.
    Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol. 2013;54:74–83.CrossRefPubMedGoogle Scholar
  107. 107.
    Huang WR, Zhang Y, Tang X. Shikonin inhibits the proliferation of human lens epithelial cells by inducing apoptosis through ROS and caspase-dependent pathway. Molecules. 2014;19:7785–97.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of immunologyTianjin Medical University Cancer Institute and HospitalTianjinChina
  2. 2.Department of BiotherapyTianjin Medical University Cancer Institute and HospitalTianjinChina
  3. 3.Key Laboratory of Cancer Immunology and BiotherapyTianjinChina
  4. 4.National Clinical Research Center of CancerTianjinChina

Personalised recommendations