Home LiteratureArticle Details
PMID: 23216602 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells.

Immunology ·Vol. 138 ·No. 2 ·2013-02-00 ·Pages 105-15

Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ

Abstract

Myeloid-derived suppressor cells (MDSC) and regulatory T (Treg) cells are major components of the immune suppressive tumour microenvironment (TME). Both cell types expand systematically in preclinical tumour models and promote T-cell dysfunction that in turn favours tumour progression. Clinical reports show a positive correlation between elevated levels of both suppressors and tumour burden. Recent studies further revealed that MDSCs can modulate the de novo development and induction of Treg cells. The overlapping target cell population of Treg cells and MDSCs is indicative for the importance and flexibility of immune suppression under pathological conditions. It also suggests the existence of common pathways that can be used for clinical interventions aiming to manipulate the TME. Elimination or reprogramming of the immune suppressive TME is one of the major current challenges in immunotherapy of cancer. Interestingly, recent findings suggest that natural killer T (NKT) cells can acquire the ability to convert immunosuppressive MDSCs into immunity-promoting antigen-presenting cells. Here we will review the cross-talk between MDSCs and other immune cells, focusing on Treg cells and NKT cells. We will consider its impact on basic and applied cancer research and discuss how targeting MDSCs may pave the way for future immunocombination therapies.

MeSH Terms
Animals Antigen-Presenting Cells/immunology,pathology Cell Communication/immunology Humans Immune Tolerance Immunotherapy/methods Myeloid Cells/immunology,pathology Natural Killer T-Cells/immunology,pathology Neoplasms/immunology,pathology,therapy T-Lymphocytes, Regulatory/immunology,pathology
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lindau Dennis
Department of Tumour Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands.
Gielen Paul
Kroesen Michiel
Wesseling Pieter
Adema Gosse J
References (108)
108 references, click to expand
  1. Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign.
    Cancer Res. 2010 Jun 1;70(11):4335-45 PMID: 20484028
  2. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A.
    Nat Immunol. 2010 Nov;11(11):1039-46 PMID: 20890286
  3. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo.
    J Exp Med. 2012 Sep 24;209(10):1713-22, S1-19 PMID: 22966003
  4. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors.
    Cancer Cell. 2005 Sep;8(3):211-26 PMID: 16169466
  5. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma.
    Cancer Res. 2011 Aug 15;71(16):5412-22 PMID: 21708957
  6. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
    Science. 2011 Mar 25;331(6024):1612-6 PMID: 21436454
  7. 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 Jan 15;66(2):1123-31 PMID: 16424049
  8. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.
    Nat Med. 2012 Aug;18(8):1254-61 PMID: 22842478
  9. Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse.
    J Immunol. 2011 Jul 15;187(2):708-17 PMID: 21670315
  10. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer.
    Clin Cancer Res. 2007 Dec 1;13(23):6947-58 PMID: 18056169
  11. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
    N Engl J Med. 2012 Jun 28;366(26):2455-65 PMID: 22658128
  12. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  13. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells.
    Cancer Res. 2009 Sep 15;69(18):7329-37 PMID: 19738057
  14. Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells.
    J Immunol. 2012 Feb 15;188(4):1592-9 PMID: 22231700
  15. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor.
    Immunity. 2010 Jun 25;32(6):790-802 PMID: 20605485
  16. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer.
    Nat Med. 2007 Jul;13(7):828-35 PMID: 17603493
  17. Improved survival with ipilimumab in patients with metastatic melanoma.
    N Engl J Med. 2010 Aug 19;363(8):711-23 PMID: 20525992
  18. Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model.
    Int J Cancer. 2008 Apr 15;122(8):1794-802 PMID: 18076066
  19. Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4⁺ T cells from patients with GI malignancy.
    Cancer Immunol Immunother. 2011 Sep;60(9):1269-79 PMID: 21604071
  20. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.
    Blood. 2008 Apr 15;111(8):4233-44 PMID: 18272812
  21. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13.
    Cancer Immunol Immunother. 2011 Oct;60(10):1419-30 PMID: 21644036
  22. Route of administration of the TLR9 agonist CpG critically determines the efficacy of cancer immunotherapy in mice.
    PLoS One. 2009 Dec 18;4(12):e8368 PMID: 20020049
  23. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.
    PLoS One. 2011;6(11):e27690 PMID: 22110722
  24. Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity.
    Blood. 2011 Dec 22;118(26):6836-44 PMID: 21967977
  25. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?
    Lancet Oncol. 2012 Jan;13(1):e32-42 PMID: 22225723
  26. Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples.
    J Immunol Methods. 2012 Jul 31;381(1-2):14-22 PMID: 22522114
  27. Subsets of myeloid-derived suppressor cells in tumor-bearing mice.
    J Immunol. 2008 Oct 15;181(8):5791-802 PMID: 18832739
  28. 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 Jan 1;70(1):99-108 PMID: 19996287
  29. Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer.
    Blood. 2008 Aug 15;112(4):1308-16 PMID: 18535199
  30. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
    Clin Cancer Res. 2010 Oct 15;16(20):5067-78 PMID: 20736326
  31. IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients.
    J Immunol. 2009 May 15;182(10):6562-8 PMID: 19414811
  32. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
    N Engl J Med. 2012 Jun 28;366(26):2443-54 PMID: 22658127
  33. FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer.
    J Clin Invest. 2011 Apr;121(4):1361-72 PMID: 21436588
  34. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model.
    Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17111-6 PMID: 21969559
  35. MIP-2 recruits NKT cells to the spleen during tolerance induction.
    J Immunol. 2001 Jan 1;166(1):313-21 PMID: 11123307
  36. Targeting natural killer cells and natural killer T cells in cancer.
    Nat Rev Immunol. 2012 Mar 22;12(4):239-52 PMID: 22437937
  37. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients.
    Cancer Res. 2001 Jun 15;61(12):4756-60 PMID: 11406548
  38. Myeloid-derived suppressor cells as regulators of the immune system.
    Nat Rev Immunol. 2009 Mar;9(3):162-74 PMID: 19197294
  39. Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein.
    J Exp Med. 2003 Jul 21;198(2):267-79 PMID: 12874260
  40. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.
    Cancer Cell. 2012 Jun 12;21(6):822-35 PMID: 22698406
  41. Helios expression is a marker of T cell activation and proliferation.
    PLoS One. 2011;6(8):e24226 PMID: 21918685
  42. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients.
    Clin Cancer Res. 2008 Oct 15;14(20):6674-82 PMID: 18927310
  43. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells.
    J Exp Med. 2011 Sep 26;208(10):1949-62 PMID: 21930770
  44. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes.
    Cancer Res. 2010 Jul 15;70(14):5728-39 PMID: 20570887
  45. Oligodeoxynucleotides stabilize Helios-expressing Foxp3+ human T regulatory cells during in vitro expansion.
    Blood. 2012 Mar 22;119(12):2810-8 PMID: 22294730
  46. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation.
    J Exp Med. 2005 Oct 3;202(7):919-29 PMID: 16186184
  47. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation.
    Cancer Res. 2011 Aug 1;71(15):5111-22 PMID: 21659460
  48. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host.
    Blood. 2007 May 15;109(10):4336-42 PMID: 17244679
  49. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway.
    Nat Immunol. 2000 Dec;1(6):515-20 PMID: 11101874
  50. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF.
    Eur J Immunol. 2010 Jan;40(1):22-35 PMID: 19941314
  51. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma.
    Neuro Oncol. 2011 Jun;13(6):591-9 PMID: 21636707
  52. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients.
    Clin Cancer Res. 2009 Mar 15;15(6):2148-57 PMID: 19276286
  53. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy.
    Cancer Immunol Immunother. 2009 Jan;58(1):49-59 PMID: 18446337
  54. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with α-galactosylceramide.
    PLoS One. 2010 Jun 25;5(6):e11311 PMID: 20593019
  55. Induction of anti-glioma natural killer cell response following multiple low-dose intracerebral CpG therapy.
    Clin Cancer Res. 2010 Jul 1;16(13):3399-408 PMID: 20570924
  56. CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis.
    PLoS One. 2011;6(6):e20702 PMID: 21695190
  57. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.
    J Exp Med. 2010 Oct 25;207(11):2439-53 PMID: 20876310
  58. Expression of Helios in peripherally induced Foxp3+ regulatory T cells.
    J Immunol. 2012 Feb 1;188(3):976-80 PMID: 22198953
  59. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors.
    J Exp Med. 2005 Mar 7;201(5):779-91 PMID: 15753211
  60. Natural innate and adaptive immunity to cancer.
    Annu Rev Immunol. 2011;29:235-71 PMID: 21219185
  61. 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 Jun 20;25(18):2546-53 PMID: 17577033
  62. Regulation of T cell receptor CD3zeta chain expression by L-arginine.
    J Biol Chem. 2002 Jun 14;277(24):21123-9 PMID: 11950832
  63. Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans.
    J Immunol. 2012 Apr 1;188(7):3000-8 PMID: 22387552
  64. CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8874-9 PMID: 12847287
  65. Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages.
    J Clin Invest. 2009 Jun;119(6):1524-36 PMID: 19411762
  66. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody.
    Cancer Res. 1999 Jul 1;59(13):3128-33 PMID: 10397255
  67. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells.
    Cancer Res. 2011 May 15;71(10):3505-15 PMID: 21444674
  68. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice.
    Clin Cancer Res. 2011 Apr 1;17(7):1765-75 PMID: 21233400
  69. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans.
    J Clin Invest. 2008 Dec;118(12):4036-48 PMID: 19033672
  70. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells.
    J Immunol. 2009 May 1;182(9):5693-701 PMID: 19380816
  71. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients.
    Cancer Res. 2006 Sep 15;66(18):9299-307 PMID: 16982775
  72. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells.
    J Exp Med. 2012 Sep 24;209(10):1723-42, S1 PMID: 22966001
  73. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils.
    PLoS One. 2012;7(2):e31524 PMID: 22348096
  74. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.
    Cancer Cell. 2012 Jun 12;21(6):836-47 PMID: 22698407
  75. Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis.
    J Immunol. 2007 Oct 15;179(8):5126-36 PMID: 17911598
  76. Recognition of bacterial glycosphingolipids by natural killer T cells.
    Nature. 2005 Mar 24;434(7032):520-5 PMID: 15791257
  77. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN.
    Cancer Cell. 2009 Sep 8;16(3):183-94 PMID: 19732719
  78. 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 Aug 1;131(3):741-51 PMID: 21898392
  79. The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells.
    J Exp Med. 1999 Apr 5;189(7):1121-8 PMID: 10190903
  80. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion.
    Cancer Res. 2005 Apr 15;65(8):3044-8 PMID: 15833831
  81. Regulation of NK cell function by human granulocyte arginase.
    J Immunol. 2009 May 1;182(9):5259-67 PMID: 19380772
  82. 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 Dec 1;198(11):1741-52 PMID: 14657224
  83. S100A9 a new marker for monocytic human myeloid-derived suppressor cells.
    Immunology. 2012 Jun;136(2):176-83 PMID: 22304731
  84. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.
    Blood. 2008 Jun 15;111(12):5610-20 PMID: 18310500
  85. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma.
    J Exp Med. 2003 Jun 16;197(12):1667-76 PMID: 12796469
  86. 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 Mar 15;69(6):2514-22 PMID: 19276342
  87. CD1 recognition by mouse NK1+ T lymphocytes.
    Science. 1995 May 12;268(5212):863-5 PMID: 7538697
  88. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes.
    Cancer Res. 2009 Feb 15;69(4):1553-60 PMID: 19201693
  89. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine.
    J Immunol. 2009 Feb 15;182(4):1818-28 PMID: 19201833
  90. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors.
    Neuro Oncol. 2009 Aug;11(4):394-402 PMID: 19028999
  91. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor.
    Hepatology. 2009 Sep;50(3):799-807 PMID: 19551844
  92. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR⁻/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma.
    Scand J Immunol. 2010 Dec;72(6):540-7 PMID: 21044128
  93. TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients.
    Neuro Oncol. 2010 Jan;12(1):7-13 PMID: 20150362
  94. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma.
    J Clin Oncol. 2007 Mar 1;25(7):862-8 PMID: 17327607
  95. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.
    J Immunol. 2004 Jan 15;172(2):989-99 PMID: 14707072
  96. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.
    J Exp Med. 2003 Dec 15;198(12):1875-86 PMID: 14676299
  97. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
    N Engl J Med. 2010 Jul 29;363(5):411-22 PMID: 20818862
  98. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists.
    Nat Med. 2007 May;13(5):552-9 PMID: 17479101
  99. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.
    J Clin Invest. 2011 Oct;121(10):4015-29 PMID: 21911941
  100. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.
    Cancer Res. 2008 Jul 1;68(13):5439-49 PMID: 18593947
  101. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells.
    J Immunol. 2010 Apr 1;184(7):3433-41 PMID: 20181882
  102. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.
    Nat Immunol. 2010 Oct;11(10):889-96 PMID: 20856220
  103. Distinct signatures of the immune responses in low risk versus high risk neuroblastoma.
    J Transl Med. 2011 Oct 06;9:170 PMID: 21978632
  104. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells.
    Cancer Res. 2006 Jul 1;66(13):6807-15 PMID: 16818658
  105. Immune therapy for cancer.
    Annu Rev Immunol. 2009;27:83-117 PMID: 19007331
  106. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1.
    J Immunol. 2009 Jan 1;182(1):240-9 PMID: 19109155
  107. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
    J Clin Oncol. 2010 Jul 1;28(19):3167-75 PMID: 20516446
  108. Coordinated regulation of myeloid cells by tumours.
    Nat Rev Immunol. 2012 Mar 22;12(4):253-68 PMID: 22437938
Article Info
Journal
Immunology
Abbr.
Immunology
ISSN
1365-2567
DOI
10.1111/imm.12036
Published
2013-02-00
Pages
105-15
Language
English
Region
England
NLM ID
0374672
PMCID
PMC3575763
Subset
IM
External Links
PubMed source DOI: 10.1111/imm.12036 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2