Cancer Immunology, Immunotherapy

, Volume 62, Issue 7, pp 1137–1148

Immune-suppressive properties of the tumor microenvironment

  • Jürgen C. Becker
  • Mads Hald Andersen
  • David Schrama
  • Per thor Straten
Review

Abstract

Solid tumors are more than an accumulation of cancer cells. Indeed, cancerous cells create a permissive microenvironment by exploiting non-transformed host cells. Thus, solid tumors rather resemble abnormal organs composed of the cancerous cells itself and the stroma providing the supportive framework. The stroma can be divided into the extracellular matrix consisting of proteoglycans, hyaluronic acid, and fibrous proteins, as well as stromal cells including mesenchymal and immune cells; moreover, it contains various peptide factors and metabolites. Here, we will focus on immune-modulating capacities of the tumor microenvironment.

Keywords

A disintegrin and metalloproteinase (ADAM) Indoleamine-2,3-dioxygenase (IDO) Arginase Hypoxia Adenosine Natural killer group 2 member D (NKG2D) ligands 

References

  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  2. 2.
    Pietras K, Östman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331. doi:10.1016/j.yexcr.2010.02.045 PubMedCrossRefGoogle Scholar
  3. 3.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867. doi:10.1038/nature01322 PubMedCrossRefGoogle Scholar
  4. 4.
    de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423. doi:10.1016/j.ccr.2005.04.014 PubMedCrossRefGoogle Scholar
  5. 5.
    Colotta F, Allavena P, Sica A et al (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073–1081. doi:10.1093/carcin/bgp127 PubMedCrossRefGoogle Scholar
  6. 6.
    Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901. doi:10.1016/j.devcel.2010.05.012 PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenberg SA (2012) Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med 4:127ps8. doi:10.1126/scitranslmed.3003634 PubMedCrossRefGoogle Scholar
  8. 8.
    Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72:3125–3130. doi:10.1158/0008-5472.CAN-11-4094 PubMedCrossRefGoogle Scholar
  9. 9.
    Bronte V, Mocellin S (2009) Suppressive influences in the immune response to cancer. J Immunother 32:1–11. doi:10.1097/CJI.0b013e3181837276 PubMedCrossRefGoogle Scholar
  10. 10.
    Andersen MH, Schrama D, thor Straten P, Becker JC (2006) PS_JID_5700001.indd. J Invest Dermatol 126:32–41. doi:10.1038/sj.jid.5700001 PubMedCrossRefGoogle Scholar
  11. 11.
    Hajishengallis G, Chavakis T (2013) Endogenous modulators of inflammatory cell recruitment. Trends Immunol 34:1–6. doi:10.1016/j.it.2012.08.003 PubMedCrossRefGoogle Scholar
  12. 12.
    Brennan PJ, Brigl M, Brenner MB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13:101–117. doi:10.1038/nri3369 PubMedCrossRefGoogle Scholar
  13. 13.
    Mantovani A (2009) The yin-yang of tumor-associated neutrophils. Cancer Cell 16:173–174. doi:10.1016/j.ccr.2009.08.014 PubMedCrossRefGoogle Scholar
  14. 14.
    Matzinger P, Kamala T (2011) Tissue-based class control: the other side of tolerance. Nat Rev Immunol 11:221–230. doi:10.1038/nri2940 PubMedCrossRefGoogle Scholar
  15. 15.
    Hofmann UB, Houben R, Bröcker E-B, Becker JC (2005) Role of matrix metalloproteinases in melanoma cell invasion. Biochimie 87:307–314. doi:10.1016/j.biochi.2005.01.013 PubMedCrossRefGoogle Scholar
  16. 16.
    Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Gen Dev 14:163–176Google Scholar
  17. 17.
    Sheu BC, Hsu SM, Ho HN et al (2001) A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res 61:237–242PubMedGoogle Scholar
  18. 18.
    Boutet P, Agüera-González S, Atkinson S et al (2009) Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol 182:49–53PubMedGoogle Scholar
  19. 19.
    Scheller J, Chalaris A, Garbers C, Rose-John S (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32:380–387. doi:10.1016/j.it.2011.05.005 PubMedCrossRefGoogle Scholar
  20. 20.
    Godefroy E, Manches O, Dréno B et al (2011) Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory TH2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell 19:333–346. doi:10.1016/j.ccr.2011.01.037 PubMedCrossRefGoogle Scholar
  21. 21.
    Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R (2011) Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 17:6985–6991. doi:10.1158/1078-0432.CCR-11-1331 PubMedCrossRefGoogle Scholar
  22. 22.
    Platten M, Wick W, Van den Eynde BJ (2012) Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 72:5435–5440. doi:10.1158/0008-5472.CAN-12-0569 PubMedCrossRefGoogle Scholar
  23. 23.
    Zou W, Restifo NP (2010) TH17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256. doi:10.1038/nri2742 PubMedCrossRefGoogle Scholar
  24. 24.
    Weinlich G, Murr C, Richardsen L et al (2007) Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology 214:8–14. doi:10.1159/000096906 PubMedCrossRefGoogle Scholar
  25. 25.
    Smith C, Chang MY, Parker KH et al (2012) IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2:722–735. doi:10.1158/2159-8290.CD-12-0014 PubMedCrossRefGoogle Scholar
  26. 26.
    Andersen MH (2012) The specific targeting of immune regulation: T-cell responses against indoleamine 2,3-dioxygenase. Cancer Immunol Immunother 61:1289–1297. doi:10.1007/s00262-012-1234-4 PubMedCrossRefGoogle Scholar
  27. 27.
    Pilotte L, Larrieu P, Stroobant V et al (2012) Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Nat Acad Sci 109:2497–2502. doi:10.1073/pnas.1113873109 PubMedCrossRefGoogle Scholar
  28. 28.
    Nowak EC, de Vries VC, Wasiuk A et al (2012) Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med 209:2127–2135. doi:10.1084/jem.20120408 PubMedCrossRefGoogle Scholar
  29. 29.
    Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654. doi:10.1038/nri1668 PubMedCrossRefGoogle Scholar
  30. 30.
    Rundhaug JE, Simper MS, Surh I, Fischer SM (2011) The role of the EP receptors for prostaglandin E2 in skin and skin cancer. Cancer Metastasis Rev 30:465–480. doi:10.1007/s10555-011-9317-9 PubMedCrossRefGoogle Scholar
  31. 31.
    Chouaib S, Messai Y, Couve S et al (2012) Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol 3:21. doi:10.3389/fimmu.2012.00021 PubMedCrossRefGoogle Scholar
  32. 32.
    Wink DA, Hines HB, Cheng RYS et al (2011) Nitric oxide and redox mechanisms in the immune response. J Leuk Biol 89:873–891. doi:10.1189/jlb.1010550 CrossRefGoogle Scholar
  33. 33.
    Jayaraman P, Parikh F, Lopez-Rivera E et al (2012) Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol 188:5365–5376. doi:10.4049/jimmunol.1103553 PubMedCrossRefGoogle Scholar
  34. 34.
    Singer K, Gottfried E, Kreutz M, Mackensen A (2011) Suppression of T-cell responses by tumor metabolites. Cancer Immunol Immunother 60:425–431. doi:10.1007/s00262-010-0967-1 PubMedCrossRefGoogle Scholar
  35. 35.
    Hirschhaeuser F, Sattler UGA, Mueller-Klieser W (2011) Lactate: a metabolic key player in cancer. Cancer Res 71:6921–6925. doi:10.1158/0008-5472.CAN-11-1457 PubMedCrossRefGoogle Scholar
  36. 36.
    Shime H, Yabu M, Akazawa T et al (2008) Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol 180:7175–7183PubMedGoogle Scholar
  37. 37.
    Cham CM, Gajewski TF (2005) Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol 174:4670–4677PubMedGoogle Scholar
  38. 38.
    Mandapathil M, Szczepanski MJ, Szajnik M et al (2010) Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 285:27571–27580. doi:10.1074/jbc.M110.127100 PubMedCrossRefGoogle Scholar
  39. 39.
    Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29:5346–5358. doi:10.1038/onc.2010.292 PubMedCrossRefGoogle Scholar
  40. 40.
    Haskó G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7:759–770. doi:10.1038/nrd2638 PubMedCrossRefGoogle Scholar
  41. 41.
    Waickman AT, Alme A, Senaldi L et al (2012) Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother 61:917–926. doi:10.1007/s00262-011-1155-7 PubMedCrossRefGoogle Scholar
  42. 42.
    Su Y, Jackson EK, Gorelik E (2011) Receptor desensitization and blockade of the suppressive effects of prostaglandin E(2) and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes. Cancer Immunol Immunother 60:111–122. doi:10.1007/s00262-010-0924-z PubMedCrossRefGoogle Scholar
  43. 43.
    Häusler SFM, Montalbán del Barrio I, Strohschein J et al (2011) Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother 60:1405–1418. doi:10.1007/s00262-011-1040-4 PubMedCrossRefGoogle Scholar
  44. 44.
    Kryczek I, Wu K, Zhao E et al (2011) IL-17+ regulatory T Cells in the microenvironments of chronic inflammation and cancer. J Immunol 186:4388–4395. doi:10.4049/jimmunol.1003251 PubMedCrossRefGoogle Scholar
  45. 45.
    Ryzhov S, Novitskiy SV, Goldstein AE et al (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+ Gr1+ Cells. J Immunol 187:6120–6129. doi:10.4049/jimmunol.1101225 PubMedCrossRefGoogle Scholar
  46. 46.
    Beavis PA, Stagg J, Darcy PK, Smyth MJ (2012) CD73: a potent suppressor of antitumor immune responses. Trends Immunol 33:231–237. doi:10.1016/j.it.2012.02.009 PubMedCrossRefGoogle Scholar
  47. 47.
    Jin D, Fan J, Wang L et al (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 70:2245–2255. doi:10.1158/0008-5472.CAN-09-3109 PubMedCrossRefGoogle Scholar
  48. 48.
    Garber K (2011) Beyond ipilimumab: new approaches target the immunological synapse. J Nat Cancer Inst 103:1079–1082. doi:10.1093/jnci/djr281 PubMedCrossRefGoogle Scholar
  49. 49.
    Cameron F, Whiteside G, Perry C (2011) Ipilimumab: first global approval. Drugs 71:1093–1104. doi:10.2165/11594010-000000000-00000 PubMedCrossRefGoogle Scholar
  50. 50.
    Callahan MK, Wolchok JD, Allison JP (2010) Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 37:473–484. doi:10.1053/j.seminoncol.2010.09.001 PubMedCrossRefGoogle Scholar
  51. 51.
    Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. doi:10.1056/NEJMoa1104621 PubMedCrossRefGoogle Scholar
  52. 52.
    Reck M, Bondarenko I, Luft A et al (2013) Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 24:75–83. doi:10.1093/annonc/mds213 PubMedCrossRefGoogle Scholar
  53. 53.
    Di Giacomo AM, Ascierto PA, Pilla L et al (2012) Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol 13:879–886. doi:10.1016/S1470-2045(12)70324-8 PubMedCrossRefGoogle Scholar
  54. 54.
    Postow MA, Callahan MK, Barker CA et al (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–931. doi:10.1056/NEJMoa1112824 PubMedCrossRefGoogle Scholar
  55. 55.
    Santegoets SJAM, Stam AGM, Lougheed SM et al (2012) T cell profiling reveals high CD4(+)CTLA-4 (+) T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother. doi:10.1007/s00262-012-1330-5 PubMedGoogle Scholar
  56. 56.
    Hodis R, Watson IR, Kryukov GV et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263. doi:10.1016/j.cell.2012.06.024 PubMedCrossRefGoogle Scholar
  57. 57.
    Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13:6681–6688. doi:10.1158/1078-0432.CCR-07-0187 PubMedCrossRefGoogle Scholar
  58. 58.
    Liakou CI, Kamat A, Tang DN et al (2008) CTLA-4 blockade increases IFNgamma-producing CD4+ ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Nat Acad Sci 105:14987–14992. doi:10.1073/pnas.0806075105 PubMedCrossRefGoogle Scholar
  59. 59.
    Ji R-R, Chasalow SD, Wang L et al (2012) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 61:1019–1031. doi:10.1007/s00262-011-1172-6 PubMedCrossRefGoogle Scholar
  60. 60.
    Hamid O, Schmidt H, Nissan A et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204. doi:10.1186/1479-5876-9-204 PubMedCrossRefGoogle Scholar
  61. 61.
    Shahabi V, Whitney G, Hamid O et al (2012) Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother 61:733–737. doi:10.1007/s00262-012-1227-3 PubMedCrossRefGoogle Scholar
  62. 62.
    la Fuente de H, Cibrián D, Sánchez-Madrid F (2012) Immunoregulatory molecules are master regulators of inflammation during the immune response. FEBS Lett 586:2897–2905. doi:10.1016/j.febslet.2012.07.032 CrossRefGoogle Scholar
  63. 63.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. doi:10.1056/NEJMoa1200690 PubMedCrossRefGoogle Scholar
  64. 64.
    Brahmer JR, Tykodi SS, Chow LQM et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. doi:10.1056/NEJMoa1200694 PubMedCrossRefGoogle Scholar
  65. 65.
    Hobo W, Novobrantseva TI, Fredrix H et al (2012) Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation. Cancer Immunol Immunother. doi:10.1007/s00262-012-1334-1 PubMedGoogle Scholar
  66. 66.
    Seliger B, Quandt D (2012) The expression, function, and clinical relevance of B7 family members in cancer. Cancer Immunol Immunother 61:1327–1341. doi:10.1007/s00262-012-1293-6 PubMedCrossRefGoogle Scholar
  67. 67.
    Yi KH, Chen L (2009) Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev 229:145–151. doi:10.1111/j.1600-065X.2009.00768.x PubMedCrossRefGoogle Scholar
  68. 68.
    Textor S, Fiegler N, Arnold A et al (2011) Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res 71:5998–6009. doi:10.1158/0008-5472.CAN-10-3211 PubMedCrossRefGoogle Scholar
  69. 69.
    Vetter CS, Groh V, thor Straten P et al (2002) Expression of stress-induced MHC class I related chain molecules on human melanoma. J Invest Dermatol 118:600–605. doi:10.1046/j.1523-1747.2002.01700.x PubMedCrossRefGoogle Scholar
  70. 70.
    Champsaur M, Lanier LL (2010) Effect of NKG2D ligand expression on host immune responses. Immunol Rev 235:267–285. doi:10.1111/j.0105-2896.2010.00893.x PubMedGoogle Scholar
  71. 71.
    Waldhauer I, Goehlsdorf D, Gieseke F et al (2008) Tumor-associated MICA is shed by ADAM proteases. Cancer Res 68:6368–6376. doi:10.1158/0008-5472.CAN-07-6768 PubMedCrossRefGoogle Scholar
  72. 72.
    Siemens DR, Hu N, Sheikhi AK et al (2008) Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 68:4746–4753. doi:10.1158/0008-5472.CAN-08-0054 PubMedCrossRefGoogle Scholar
  73. 73.
    Barsoum IB, Hamilton TK, Li X et al (2011) Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide. Cancer Res 71:7433–7441. doi:10.1158/0008-5472.CAN-11-2104 PubMedCrossRefGoogle Scholar
  74. 74.
    Pruessmeyer J, Ludwig A (2009) The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol 20:164–174. doi:10.1016/j.semcdb.2008.09.005 PubMedCrossRefGoogle Scholar
  75. 75.
    Paschen A, Sucker A, Hill B et al (2009) Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B. Clin Cancer Res 15:5208–5215. doi:10.1158/1078-0432.CCR-09-0886 PubMedCrossRefGoogle Scholar
  76. 76.
    Benitez AC, Dai Z, Mann HH et al (2011) Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells. Proc Nat Acad Sci 108:4081–4086. doi:10.1073/pnas.1018603108 PubMedCrossRefGoogle Scholar
  77. 77.
    Rak J (2013) Extracellular vesicles—biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol 4:21. doi:10.3389/fphar.2013.00021 PubMedCrossRefGoogle Scholar
  78. 78.
    Taylor DD, Doellgast GJ (1979) Quantitation of peroxidase-antibody binding to membrane fragments using column chromatography. Anal Biochem 98:53–59PubMedCrossRefGoogle Scholar
  79. 79.
    Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454. doi:10.1007/s00281-010-0234-8 PubMedCrossRefGoogle Scholar
  80. 80.
    Filipazzi P, Bürdek M, Villa A et al (2012) Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Sem Cancer Biol 22:342–349. doi:10.1016/j.semcancer.2012.02.005 CrossRefGoogle Scholar
  81. 81.
    Huber V, Filipazzi P, Iero M et al (2008) More insights into the immunosuppressive potential of tumor exosomes. J Transl Med 6:63. doi:10.1186/1479-5876-6-63 PubMedCrossRefGoogle Scholar
  82. 82.
    van der Heyde HC, Gramaglia I, Combes V et al (2011) Flow cytometric analysis of microparticles. Methods Mol Biol 699:337–354. doi:10.1007/978-1-61737-950-5_16 PubMedCrossRefGoogle Scholar
  83. 83.
    Whiteside TL (2013) Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 41:245–251. doi:10.1042/BST20120265 PubMedCrossRefGoogle Scholar
  84. 84.
    Xiang X, Poliakov A, Liu C et al (2009) Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 124:2621–2633. doi:10.1002/ijc.24249 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jürgen C. Becker
    • 1
  • Mads Hald Andersen
    • 2
  • David Schrama
    • 1
  • Per thor Straten
    • 2
  1. 1.Department of General DermatologyMedical University of GrazGrazAustria
  2. 2.Department of Hematology, Center for Cancer Immune Therapy (CCIT)University Hospital HerlevHerlevDenmark

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