1932

Abstract

Despite continual hints from preclinical and clinical research of its relevance, cancer immunology existed for many years at the periphery of cancer therapeutics. It is now the focus of intense and widespread interest after observations that blocking the activity of inhibitory receptors on T cells, known as T cell checkpoints, elicits durable clinical responses in many patients. The urgent challenge is now to understand the tissue-protective cellular elements of the tumor microenvironment (TME) that explain why the majority of patients do not respond to T cell checkpoint therapy. Analysis of human cancers and mouse models has shown that this nonresponsiveness is caused by the exclusion of T cells from the vicinity of cancer cells and that cells of the TME mediate this restriction. This review examines the immunosuppressive functions of the cells of the TME and discusses the steps of the antitumor immune reaction that, if inhibited, would diminish intratumoral T cell accumulation.

Keyword(s): CXCL12CXCR3FAPmonocytePD-1
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/content/journals/10.1146/annurev-cancerbio-050216-034359
2017-03-06
2024-12-03
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Literature Cited

  1. Alexandre YO, Ghilas S, Sanchez C, Le Bon A, Crozat K, Dalod M. 2016. XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses. J. Exp. Med. 213:75–92 [Google Scholar]
  2. Bannard O, Kraman M, Fearon D. 2009a. Pathways of memory CD8+ T-cell development. Eur. J. Immunol. 392083–87 [Google Scholar]
  3. Bannard O, Kraman M, Fearon DT. 2009b. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 323:505–9 [Google Scholar]
  4. Bannard O, Kraman M, Fearon DT. 2010. Cutting edge: Virus-specific CD8+ T cell clones and the maintenance of replicative function during a persistent viral infection. J. Immunol. 185:7141–45 [Google Scholar]
  5. Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. 2015. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol. 16:850–58 [Google Scholar]
  6. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL. et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 3662455–65 [Google Scholar]
  7. Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL. et al. 2014. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26638–52 [Google Scholar]
  8. Chang Q, Jurisica I, Do T, Hedley DW. 2011. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 713110–20 [Google Scholar]
  9. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI. et al. 2010. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207:2439–53 [Google Scholar]
  10. Deng L, Liang H, Xu M, Yang X, Burnette B. et al. 2014. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41843–52 [Google Scholar]
  11. Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S. et al. 2014. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515:134–37 [Google Scholar]
  12. Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP. et al. 2011. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208:1989–2003 [Google Scholar]
  13. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P. et al. 2002. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–54 [Google Scholar]
  14. Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C. et al. 2012. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell 21:402–17 [Google Scholar]
  15. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A. et al. 2013. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. PNAS 110:20212–17 [Google Scholar]
  16. Ferris ST, Carrero JA, Mohan JF, Calderon B, Murphy KM, Unanue ER. 2014. A minor subset of Batf3-dependent antigen-presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes. Immunity 41:657–69 [Google Scholar]
  17. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM. et al. 2011. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208:2005–16 [Google Scholar]
  18. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. 2012. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12253–68 [Google Scholar]
  19. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B. et al. 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 3131960–64 [Google Scholar]
  20. Garin-Chesa P, Old LJ, Rettig WJ. 1990. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. PNAS 877235–39 [Google Scholar]
  21. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP. et al. 2014. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–81 [Google Scholar]
  22. Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI. et al. 2016. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6270–85 [Google Scholar]
  23. Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. 2001. Donor-derived IP-10 initiates development of acute allograft rejection. J. Exp. Med. 193975–80 [Google Scholar]
  24. Hancock WW, Lu B, Gao W, Csizmadia V, Faia K. et al. 2000. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J. Exp. Med. 192:1515–20 [Google Scholar]
  25. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M. et al. 2009. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 693077–85 [Google Scholar]
  26. Hashimoto D, Miller J, Merad M. 2011. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35323–35 [Google Scholar]
  27. Headley MB, Bins A, Nip A, Roberts EW, Looney MR. et al. 2016. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531513–17 [Google Scholar]
  28. Heaton SM, Borg NA, Dixit VM. 2016. Ubiquitin in the activation and attenuation of innate antiviral immunity. J. Exp. Med. 2016. 213:1–13 [Google Scholar]
  29. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O. et al. 2014. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–67 [Google Scholar]
  30. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H. et al. 2008. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322:1097–100 [Google Scholar]
  31. Hirano F, Kaneko K, Tamura H, Dong H, Wang S. et al. 2005. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 651089–96 [Google Scholar]
  32. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA. et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363711–23 [Google Scholar]
  33. Jones PH, Watt FM. 1993. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73713–24 [Google Scholar]
  34. Josefowicz SZ, Lu LF, Rudensky AY. 2012. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30531–64 [Google Scholar]
  35. Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP. et al. 2015. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity 43579–90 [Google Scholar]
  36. Joyce JA, Fearon DT. 2015. T cell exclusion, immune privilege, and the tumor microenvironment. Science 34874–80 [Google Scholar]
  37. Kallies A, Hawkins ED, Belz GT, Metcalf D, Hommel M. et al. 2006. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7466–74 [Google Scholar]
  38. Kedzierska K, La Gruta NL, Turner SJ, Doherty PC. 2006. Establishment and recall of CD8+ T-cell memory in a model of localized transient infection. Immunol. Rev. 211:133–45 [Google Scholar]
  39. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L. et al. 2010. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330827–30 [Google Scholar]
  40. Krummel MF, Allison JP. 1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182:459–65 [Google Scholar]
  41. Leach DR, Krummel MF, Allison JP. 1996. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–36 [Google Scholar]
  42. Lee KG, Kim SS, Kui L, Voon DC, Mauduit M. et al. 2015. Bruton's tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response. Cell Rep 10:1055–65 [Google Scholar]
  43. Lesokhin AM, Hohl TM, Kitano S, Cortez C, Hirschhorn-Cymerman D. et al. 2012. Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 72876–86 [Google Scholar]
  44. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM. et al. 2015. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 543–51 [Google Scholar]
  45. Martins GA, Cimmino L, Shapiro-Shelef M, Szabolcs M, Herron A. et al. 2006. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7457–65 [Google Scholar]
  46. McGill J, Legge KL. 2009. Cutting edge: Contribution of lung-resident T cell proliferation to the overall magnitude of the antigen-specific CD8 T cell response in the lungs following murine influenza virus infection. J. Immunol. 183:4177–81 [Google Scholar]
  47. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R. et al. 2016. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 3511463–69 [Google Scholar]
  48. Meiser A, Mueller A, Wise EL, McDonagh EM, Petit SJ. et al. 2008. The chemokine receptor CXCR3 is degraded following internalization and is replenished at the cell surface by de novo synthesis of receptor. J. Immunol. 180:6713–24 [Google Scholar]
  49. Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB. et al. 2015. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat. Commun. 67458 [Google Scholar]
  50. Monach PA, Meredith SC, Siegel CT, Schreiber H. 1995. A unique tumor antigen produced by a single amino acid substitution. Immunity 245–59 [Google Scholar]
  51. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR. et al. 2014. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20:607–15 [Google Scholar]
  52. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K. et al. 1998. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 583491–94 [Google Scholar]
  53. Nancy P, Tagliani E, Tay CS, Asp P, Levy DE, Erlebacher A. 2012. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 3361317–21 [Google Scholar]
  54. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–51 [Google Scholar]
  55. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S. et al. 2014. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211:781–90 [Google Scholar]
  56. Noy R, Pollard JW. 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 4149–61 [Google Scholar]
  57. Okazaki T, Honjo T. 2007. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19:813–24 [Google Scholar]
  58. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T. et al. 2005. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121335–48 [Google Scholar]
  59. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC. et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25719–34 [Google Scholar]
  60. Paludan SR, Bowie AG. 2013. Immune sensing of DNA. Immunity 38870–80 [Google Scholar]
  61. Pekarek LA, Starr BA, Toledano AY, Schreiber H. 1995. Inhibition of tumor growth by elimination of granulocytes. J. Exp. Med. 181:435–40 [Google Scholar]
  62. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S. et al. 2015. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249–53 [Google Scholar]
  63. Peske JD, Thompson ED, Gemta L, Baylis RA, Fu YX, Engelhard VH. 2015. Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat. Commun. 67114 [Google Scholar]
  64. Platten M, Wick W, Van den Eynde BJ. 2012. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res 725435–40 [Google Scholar]
  65. Pommier A, Audemard A, Durand A, Lengagne R, Delpoux A. et al. 2013. Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells. PNAS 110:13085–90 [Google Scholar]
  66. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y. et al. 2014. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–62 [Google Scholar]
  67. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V. et al. 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348124–28 [Google Scholar]
  68. Rosenberg SA, Restifo NP. 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 34862–68 [Google Scholar]
  69. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM. et al. 2014. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26623–37 [Google Scholar]
  70. Rutishauser RL, Kaech SM. 2010. Generating diversity: transcriptional regulation of effector and memory CD8 T-cell differentiation. Immunol. Rev. 235:219–33 [Google Scholar]
  71. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K. et al. 2009. Activation of innate immune antiviral responses by Nod2. Nat. Immunol. 10:1073–80 [Google Scholar]
  72. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R. 2015. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. PNAS 112:E966–72 [Google Scholar]
  73. Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R. et al. 2016. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44924–38 [Google Scholar]
  74. Santos AM, Jung J, Aziz N, Kissil JL, Puré E. 2009. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J. Clin. Investig. 119:3613–25 [Google Scholar]
  75. Schietinger A, Greenberg PD. 2014. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol 3551–60 [Google Scholar]
  76. Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JI. et al. 2016. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45:389–401 [Google Scholar]
  77. Schumacher TN, Schreiber RD. 2015. Neoantigens in cancer immunotherapy. Science 34869–74 [Google Scholar]
  78. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW. et al. 2008. Epitope landscape in breast and colorectal cancer. Cancer Res 68889–92 [Google Scholar]
  79. Seung E, Cho JL, Sparwasser T, Medoff BD, Luster AD. 2011. Inhibiting CXCR3-dependent CD8+ T cell trafficking enhances tolerance induction in a mouse model of lung rejection. J. Immunol. 186:6830–38 [Google Scholar]
  80. Sharma P, Allison JP. 2015. The future of immune checkpoint therapy. Science 348:56–61 [Google Scholar]
  81. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K. et al. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210:1695–710 [Google Scholar]
  82. Strachan DC, Ruffell B, Oei Y, Bissell MJ, Coussens LM. et al. 2013. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells. Oncoimmunology 2e26968 [Google Scholar]
  83. Terabe M, Berzofsky JA. 2014. The immunoregulatory role of type I and type II NKT cells in cancer and other diseases. Cancer Immunol. Immunother. 63199–213 [Google Scholar]
  84. Thaventhiran JE, Hoffmann A, Magiera L, de la Roche M, Lingel H. et al. 2012. Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+ T cell. PNAS 109:E2223–29 [Google Scholar]
  85. Thompson ED, Enriquez HL, Fu YX, Engelhard VH. 2010. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J. Exp. Med. 207:1791–804 [Google Scholar]
  86. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3541–47 [Google Scholar]
  87. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC. et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 3662443–54 [Google Scholar]
  88. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S. et al. 2015. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 3501387–90 [Google Scholar]
  89. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ. et al. 2014. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–71 [Google Scholar]
  90. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C. et al. 2015. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350207–11 [Google Scholar]
  91. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E. et al. 1991. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–47 [Google Scholar]
  92. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS. et al. 2014. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2154–66 [Google Scholar]
  93. Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C. et al. 1995. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269:1281–84 [Google Scholar]
  94. Woo SR, Corrales L, Gajewski TF. 2015. Innate immune recognition of cancer. Annu. Rev. Immunol. 33445–74 [Google Scholar]
  95. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ. et al. 2014. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41830–42 [Google Scholar]
  96. Zelenay S, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N. et al. 2015. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162:1257–70 [Google Scholar]
  97. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M. et al. 2003. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348203–13 [Google Scholar]
  98. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL. et al. 2014. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 745057–69 [Google Scholar]
  99. Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Liénard D. et al. 2004. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 642865–73 [Google Scholar]
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