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Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

  • Published:
Cancer Microenvironment

Abstract

There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular anti-tumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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References

  1. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB (2010) A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 7:699–731

    Article  Google Scholar 

  2. Pino MS, Chung DC (2010) The chromosomal instability pathway in colon cancer. Gastroenterology 6:2059–2072

    Article  Google Scholar 

  3. Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 3:153–162

    Article  Google Scholar 

  4. Poulogiannis G, Frayling IM, Arends MJ (2010) DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology 2:167–179

    Article  Google Scholar 

  5. Grady W, Rajput A, Lutterbaugh J, Markowitz S (2001) Detection of aberrantly methylated hMLH1 promoter DNA in the serum of patients with microsatellite unstable colon cancer. Cancer Res 3:900–902

    Google Scholar 

  6. Edmonston T, Cuesta K, Burkholder S, Barusevicius A, Rose D, Kovatich A, Boman B, Fry R, Fishel R, Palazzo J (2000) Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. Hum Pathol 12:1506–1514

    Article  Google Scholar 

  7. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe Toyota M, Baylin SB, Issa JP (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 10:2307–2312

    Google Scholar 

  8. Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 5:1883–1886

    Article  Google Scholar 

  9. Locker G, Hamilton S, Harris J, Jessup J, Kemeny N, Macdonald J, Somerfield M, Hayes D, Bast R (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 33:5313–5327

    Article  Google Scholar 

  10. Pages F, Berger A, Camus M, Sanchez Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc P, Trajanoski Z, Fridman W, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 25:2654–2666

    Article  Google Scholar 

  11. Pages F, Galon J, Fridman WH (2008) The essential role of the in situ immune reaction in human colorectal cancer. J Leukoc Biol 4:981–987

    Article  Google Scholar 

  12. Sengupta N, MacFie TS, MacDonald TT, Pennington D, Silver AR (2010) Cancer immunoediting and “spontaneous” tumor regression. Pathol Res Pract 1:1–8

    Article  Google Scholar 

  13. Shunyakov L, Ryan CK, Sahasrabudhe DM, Khorana AA (2004) The influence of host response on colorectal cancer prognosis. Clin Colorectal Cancer 1:38–45

    Article  Google Scholar 

  14. Loose D, Van de Wiele C (2009) The immune system and cancer. Cancer Biother Radiopharm 3:369–376

    Article  Google Scholar 

  15. Watson NF, Ramage JM, Madjd Z, Spendlove I, Ellis IO, Scholefield JH, Durrant LG (2006) Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int.J. Cancer 1:6–10

    Google Scholar 

  16. Titu LV, Monson JR, Greenman J (2002) The role of CD8(+) T cells in immune responses to colorectal cancer. Cancer Immunol Immunother 5:235–247

    Article  Google Scholar 

  17. Atkinson EA, Bleackley RC (1995) Mechanisms of lysis by cytotoxic T cells. Crit Rev Immunol 3–4:359–384

    Google Scholar 

  18. Atreya I, Neurath MF (2008) Immune cells in colorectal cancer: prognostic relevance and therapeutic strategies. Expert Rev Anticancer Ther 4:561–572

    Article  Google Scholar 

  19. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 3:254–265

    Article  Google Scholar 

  20. Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM (2003) Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with Stage II and Stage III colon carcinoma: a role for the host response in prognosis. Cancer 4:960–968

    Article  Google Scholar 

  21. Oberg A, Samii S, Stenling R, Lindmark G (2002) Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors. Int J Colorectal Dis 1:25–29

    Google Scholar 

  22. Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y, Gabbert HE (2003) Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep 2:309–313

    Google Scholar 

  23. Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM, Zhang X, Pang ZZ, Wan DS, Zeng YX, Zhang XS (2010) The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med 13

  24. Kang JC, Chen JS, Lee CH, Chang JJ, Shieh YS (2010) Intratumoral macrophage counts correlate with tumor progression in colorectal cancer. J Surg Oncol 3:242–248

    Article  Google Scholar 

  25. Pancione M, Forte N, Sabatino L, Tomaselli E, Parente D, Febbraro A, Colantuoni V (2009) Reduced beta-catenin and peroxisome proliferator-activated receptor-gamma expression levels are associated with colorectal cancer metastatic progression: correlation with tumor-associated macrophages, cyclooxygenase 2, and patient outcome. Hum Pathol 5:714–725

    Article  Google Scholar 

  26. Kaler P, Galea V, Augenlicht L, Klampfer L (2010) Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells. PLoS One 7:e11700

    Article  Google Scholar 

  27. Kaler P, Godasi BN, Augenlicht L, Klampfer L (2009) The NF-kappaB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1beta. Cancer Microenviron 1:69–80

    Article  Google Scholar 

  28. Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC (2010) Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 8:2699–2714

    Article  Google Scholar 

  29. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2:411–421

    Article  Google Scholar 

  30. Green CE, Liu T, Montel V, Hsiao G, Lester RD, Subramaniam S, Gonias SL, Klemke RL (2009) Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization. PLoS One 8:e6713

    Article  Google Scholar 

  31. Jedinak A, Dudhgaonkar S, Sliva D (2010) Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 3:242–249

    Article  Google Scholar 

  32. Mazzolini G, Murillo O, Atorrasagasti C, Dubrot J, Tirapu I, Rizzo M, Arina A, Alfaro C, Azpilicueta A, Berasain C, Perez-Gracia JL, Gonzalez A, Melero I (2007) Immunotherapy and immunoescape in colorectal cancer. World J Gastroenterol 44:5822–5831

    Google Scholar 

  33. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ (2006) CD4 + CD25 + FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE e129

  34. Yaqub S, Henjum K, Mahic M, Jahnsen FL, Aandahl EM, Bjornbeth BA, Tasken K (2008) Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner. Cancer Immunol Immunother 6:813–821

    Article  Google Scholar 

  35. Correale P, Cusi MG, Micheli L, Nencini C, Del Vecchio MT, Torino F, Aquino A, Bonmassar E, Francini G, Giorgi G (2006) Chemo-immunotherapy of colorectal carcinoma: preclinical rationale and clinical experience. Invest New Drugs 2:99–110

    Article  Google Scholar 

  36. Koch M, Beckhove P, Op den Winkel J, Autenrieth D, Wagner P, Nummer D, Specht S, Antolovic D, Galindo L, Schmitz-Winnenthal FH, Schirrmacher V, Buchler MW, Weitz J (2006) Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ. Ann Surg 6:986–992

    Article  Google Scholar 

  37. Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S, Scheper RJ, Meijer CJ, Bloemena E, Ransom JH, Hanna MG, Pinedo HM (1999) Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 9150:345–350

    Article  Google Scholar 

  38. Svennevig JL, Lunde OC, Holter J, Bjorgsvik D (1984) Lymphoid infiltration and prognosis in colorectal carcinoma. Br J Cancer 3:375–377

    Article  Google Scholar 

  39. Jass JR (1986) Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 6:585–589

    Article  Google Scholar 

  40. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma VM (1997) Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 3:318–324

    Article  Google Scholar 

  41. Ohtani H (2007) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 4

  42. Milasiene V, Stratilatovas E, Norkiene V, Jonusauskaite R (2005) Lymphocyte subsets in peripheral blood as prognostic factors in colorectal cancer. J BUON 2:261–264

    Google Scholar 

  43. Qiu H, Xiao-Jun W, Zhi-Wei Z, Gong C, Guo-Qiang W, Li-Yi Z, Yuan-Fang L, Rajiv-Prasad K (2009) The prognostic significance of peripheral T-lymphocyte subsets and natural killer cells in patients with colorectal cancer. Hepatogastroenterology 94–95:1310–1315

    Google Scholar 

  44. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 5795:1960–1964

    Article  Google Scholar 

  45. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 35:5944–5951

    Article  Google Scholar 

  46. Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, Berger MR, Galle PR, Herr W, Neurath MF (2007) The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut 11:1572–1578

    Article  Google Scholar 

  47. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A (2009) CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol 9:877–884

    Article  Google Scholar 

  48. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 16:3491–3494

    Google Scholar 

  49. Linnebacher M, Gebert J, Rudy W, Woerner S, Yuan Y, Bork P, von Knebel Doeberitz M (2001) Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer 1:6–11

    Article  Google Scholar 

  50. Diederichsen AC, Hjelmborg JB, Christensen PB, Zeuthen J, Fenger C (2003) Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother 7:423–428

    Article  Google Scholar 

  51. Menon AG, Janssen-van Rhijn CM, Morreau H, Putter H, Tollenaar RA, van de Velde CJH, Fleuren GJ, Kuppen PJ (2004) Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis. Lab Invest 4:493–501

    Article  Google Scholar 

  52. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, Satomi S (2004) Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 9:1711–1717

    Google Scholar 

  53. Baker K, Chong G, Foulkes WD, Jass JR (2006) Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial lymphocytes. Histopathology 4:371–380

    Article  Google Scholar 

  54. Wagner P, Koch M, Nummer D, Palm S, Galindo L, Autenrieth D, Rahbari N, Schmitz-Winnenthal FH, Schirrmacher V, Buchler MW, Beckhove P, Weitz J (2008) Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer. Ann Surg Oncol 8:2310–2317

    Article  Google Scholar 

  55. Morris M, Platell C, Iacopetta B (2008) Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. Clin Cancer Res 5:1413–1417

    Article  Google Scholar 

  56. Lugli A, Karamitopoulou E, Panayiotides I, Karakitsos P, Rallis G, Peros G, Iezzi G, Spagnoli G, Bihl M, Terracciano L, Zlobec I (2009) CD8+ lymphocytes/tumour-budding index: an independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer. Br J Cancer 8:1382–1392

    Article  Google Scholar 

  57. Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y, Shima K, Glickman JN, Ferrone CR, Mino-Kenudson M, Tanaka N, Dranoff G, Giovannucci EL, Fuchs CS (2009) Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin Cancer Res 20:6412–6420

    Article  Google Scholar 

  58. Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman WH, Pages F, Trajanoski Z, Galon J (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 4:1429–1440

    Article  Google Scholar 

  59. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC (2009) Comparison of the prognostic value of inflammation-based pathologic and biochemical criteria in patients undergoing potentially curative resection for colorectal cancer. Ann Surg 5:788–793

    Article  Google Scholar 

  60. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC (2009) Tumour inflammatory infiltrate predicts survival following curative resection for node-negative colorectal cancer. Eur J Cancer 12:2138–2145

    Article  Google Scholar 

  61. Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, Sozaki M, Tanaka M, Onishi H, Morisaki T, Katano M (2010) Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 5:653–661

    Article  Google Scholar 

  62. Zimmermann T, Moehler M, Gockel I, Sgourakis GG, Biesterfeld S, Muller M, Berger MR, Lang H, Galle PR, Schimanski CC (2010) Low expression of chemokine receptor CCR5 in human colorectal cancer correlates with lymphatic dissemination and reduced CD8+ T-cell infiltration. Int J Colorectal Dis 4:417–424

    Article  Google Scholar 

  63. Saurer L, Mueller C (2009) T cell-mediated immunoregulation in the gastrointestinal tract. Allergy 4:505–519

    Article  Google Scholar 

  64. Kumar S, Chang EY, Frankhouse J, Dorsey PB, Lee RG, Johnson N (2009) Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator for adjuvant therapy in colon cancer. Arch Surg 9:835–840

    Google Scholar 

  65. Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S (2004) Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 4:469–475

    Article  Google Scholar 

  66. Saeterdal I, Bjorheim J, Lislerud K, Gjertsen M, Bukholm I, Olsen O, Nesland J, Eriksen J, Moller M, Lindblom A, Gaudernack G (2001) Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci USA 23:13255–13260

    Article  Google Scholar 

  67. Banerjea A, Bustin S, Dorudi S (2005) The immunogenicity of colorectal cancers with high-degree microsatellite instability. World J Surg Oncol 1:26

    Article  Google Scholar 

  68. Ishikawa T, Fujita T, Suzuki Y, Okabe S, Yuasa Y, Iwai T, Kawakami Y (2003) Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Cancer Res 17:5564–5572

    Google Scholar 

  69. Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel DM (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 4:988–997

    Article  Google Scholar 

  70. Tougeron D, Fauquembergue E, Rouquette A, Le PF, Sesboue R, Laurent M, Berthet P, Mauillon J, Di FF, Sabourin JC, Michel P, Tosi M, Frebourg T, Latouche JB (2009) Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol 9:1186–1195

    Article  Google Scholar 

  71. Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, Vecchiato N, Macri E, Fornasarig M, Boiocchi M (1999) High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 6:1805–1813

    Article  Google Scholar 

  72. Guidoboni M, Gafa R, Viel A, Doglioni C, Russo A, Santini A, Del Tin L, Macri E, Lanza G, Boiocchi M, Dolcetti R (2001) Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol 1:297–304

    Article  Google Scholar 

  73. Michael-Robinson JM, Biemer-Huttmann AE, Purdie DM, Walsh MD, Simms LA, Biden KG, Young JP, Leggett BA, Jass JR, Radford-Smith GL (2001) Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 360–366

  74. Buckowitz A, Knaebel H, Benner A, Blaker H, Gebert J, Kienle P, von Knebel Doeberitz M, Kloor M (2005) Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 9:1746–1753

    Article  Google Scholar 

  75. Houston AM, Michael-Robinson JM, Walsh MD, Cummings MC, Ryan AE, Lincoln D, Pandeya N, Jass JR, Radford-Smith GL, O’Connell J (2008) The “Fas counterattack” is not an active mode of tumor immune evasion in colorectal cancer with high-level microsatellite instability. Hum Pathol 2:243–250

    Article  Google Scholar 

  76. Prall F (2007) Tumour budding in colorectal carcinoma. Histopathology 1:151–162

    Article  Google Scholar 

  77. Wang LM, Kevans D, Mulcahy H, O’Sullivan J, Fennelly D, Hyland J, O’Donoghue D, Sheahan K (2009) Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am.J Surg. Pathol 1:134–141

    Google Scholar 

  78. Baker K, Zlobec I, Tornillo L, Terracciano L, Jass JR, Lugli A (2007) Differential significance of tumour infiltrating lymphocytes in sporadic mismatch repair deficient versus proficient colorectal cancers: a potential role for dysregulation of the transforming growth factor-beta pathway. Eur J Cancer 3:624–631

    Article  Google Scholar 

  79. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB (2010) Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 19

  80. Prall F, Duhrkop T, Weirich V, Ostwald C, Lenz P, Nizze H, Barten M (2004) Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Human Pathol 7:808–816

    Article  Google Scholar 

  81. Shapira S, Lisiansky V, Arber N, Kraus S (2010) Targeted immunotherapy for colorectal cancer: monoclonal antibodies and immunotoxins. Expert Opin Investig Drugs S67-S77

  82. Schulze T, Kemmner W, Weitz J, Wernecke KD, Schirrmacher V, Schlag PM (2009) Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother 1:61–69

    Article  Google Scholar 

  83. Hanna MG Jr, Hoover HC Jr, Pinedo HM, Finer M (2006) Active specific immunotherapy with autologous tumor cell vaccines for stage II colon cancer: logistics, efficacy, safety and immunological Pharmacodynamics. Hum Vaccin 4:185–191

    Article  Google Scholar 

  84. Wen Y, Wang CT, Ma TT, Li ZY, Zhou LN, Mu B, Leng F, Shi HS, Li YO, Wei YQ (2010) Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci

  85. Chi CH, Wang YS, Yang CH, Chi KH (2010) Neoadjuvant immunotherapy enhances radiosensitivity through natural killer cell activation. Cancer Biother Radiopharm 1:39–45

    Article  Google Scholar 

  86. Saha A, Chatterjee SK (2010) Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer. Scand J Immunol 2:70–82

    Article  Google Scholar 

  87. Menon AG, Morreau H, Tollenaar RA, Alphenaar E, van Puijenbroek M, Putter H, van de Velde CJH, Fleuren GJ, Kuppen PJK, Rhijn CM (2002) Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients. Lab Invest 12:1725–1733

    Google Scholar 

  88. Lovig T, Andersen SN, Thorstensen L, Diep CB, Meling GI, Lothe RA, Rognum TO (2002) Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis. Br J Cancer 7:756–762

    Article  Google Scholar 

  89. Takemoto N, Konishi F, Yamashita K, Kojima M, Furukawa T, Miyakura Y, Shitoh K, Nagai H (2004) The correlation of microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration. Jpn J Clin Oncol 2:90–98

    Article  Google Scholar 

  90. Kloor M, Becker C, Benner A, Woerner SM, Gebert J, Ferrone S, von Knebel Doeberitz M (2005) Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res 14:6418–6424

    Article  Google Scholar 

  91. Dierssen JW, de Miranda NF, Ferrone S, van Puijenbroek M, Cornelisse CJ, Fleuren GJ, van Wezel T, Morreau H (2007) HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer 33

  92. Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, von Knebel DM, Kloor M (2008) High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer 11:1867–1873

    Article  Google Scholar 

  93. Banerjea A, Hands RE, Powar MP, Bustin SA, Dorudi S (2009) Microsatellite and chromosomal stable colorectal cancers demonstrate poor immunogenicity and early disease recurrence. Colorectal Dis 6:601–608

    Article  Google Scholar 

  94. Drescher KM, Sharma P, Watson P, Gatalica Z, Thibodeau SN, Lynch HT (2009) Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam Cancer 3:231–239

    Article  Google Scholar 

  95. Chang EY, Dorsey PB, Frankhouse J, Lee RG, Walts D, Johnson W, Anadiotis G, Johnson N (2009) Combination of microsatellite instability and lymphocytic infiltrate as a prognostic indicator in colon cancer. Arch Surg 6:511–515

    Google Scholar 

  96. Sinicrope FA, Sargent DJ (2009) Clinical implications of microsatellite instability in sporadic colon cancers. Curr Opin Oncol 4:369–373

    Article  Google Scholar 

  97. Loddenkemper C, Schernus M, Noutsias M, Stein H, Thiel E, Nagorsen D (2006) In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer. J Transl Med 52

  98. Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, Warren BF, Piris J, Roncador G, Fox SB, Banham AH, Cerundolo V (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7

  99. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2:186–192

    Article  Google Scholar 

  100. Kirk R (2010) Risk factors. CD8+:FOXP3+ cell ratio is a novel survival marker for colorectal cancer. Nat Rev Clin Oncol 6:299

    Article  Google Scholar 

  101. Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette MT, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, Farcet JP, Sobhani I (2008) High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut 6:772–779

    Article  Google Scholar 

  102. Loddenkemper C, Nagorsen D, Zeitz M (2008) Foxp3 and microsatellite stability phenotype in colorectal cancer. Gut 6:725–726

    Article  Google Scholar 

  103. Frey DM, Droese RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L (2010) High frequency of tumor-infiltrating FOXP3+ regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 11:2635–2643

    Google Scholar 

  104. Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D, Reissfelder C, Antolovic D, Aigner M, Koch M, Beckhove P (2009) Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 11:3311–3321

    Google Scholar 

  105. Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Menegaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J (2009) Identification of CD8 + CD25 + Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 4:520–529

    Article  Google Scholar 

  106. Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, Koga K, Nakamura M, Tanaka M, Morisaki T, Katano M (2009) The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 3:881–888

    Google Scholar 

  107. Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, Weitz J, Koch M, Halverson AL, Bentrem DJ, Khazaie K (2010) In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci USA 14:6430–6435

    Article  Google Scholar 

  108. Lee WS, Park S, Lee WY, Yun SH, Chun HK (2010) Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer

  109. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L, Tassone P, Francini G, Tagliaferri P (2010) Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 4:435–441

    Article  Google Scholar 

  110. Deng L, Zhang H, Luan Y, Zhang J, Xing Q, Dong S, Wu X, Liu M, Wang S (2010) Accumulation of foxp3+ T regulatory cells in draining lymph nodes correlates with disease progression and immune suppression in colorectal cancer patients. Clin Cancer Res 16:4105–4112

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Vanessa Deschoolmeester, Marc Baay, Filip Lardon, Patrick Pauwels & Marc Peeters

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  1. Vanessa Deschoolmeester
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  2. Marc Baay
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  3. Filip Lardon
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  4. Patrick Pauwels
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Correspondence to Vanessa Deschoolmeester.

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Deschoolmeester, V., Baay, M., Lardon, F. et al. Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI. Cancer Microenvironment 4, 377–392 (2011). https://doi.org/10.1007/s12307-011-0068-5

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