Prognostic value of innate and adaptive immunity in colorectal cancer

World Journal of Gastroenterology

Volumn 19, Issue 2, 2013, Pages 174-184

  Grizzi, Fabio ^a   Bianchi, Paolo ^a   Malesci, Alberto ^a,b   Laghi, Luigi ^a  

^a HUMANITAS CLINICAL AND RESEARCH CENTER   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

Author keywords

Colorectal cancer; Immunity; Inflammation; Metastasis; Prognosis

Indexed keywords

CATHEPSIN; CD20 ANTIGEN; CD68 ANTIGEN; CD83 ANTIGEN; COLONY STIMULATING FACTOR 1; CXCL16 CHEMOKINE; CXCL3 CHEMOKINE; EPIDERMAL GROWTH FACTOR; EPITHELIAL DERIVED NEUTROPHIL ACTIVATING FACTOR 78; GAMMA INTERFERON; GROWTH ARREST SPECIFIC PROTEIN 6; INTERFERON REGULATORY FACTOR 1; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 1BETA; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 8; METALLOPROTEINASE; MONOCYTE CHEMOTACTIC PROTEIN 1; PERFORIN; SEMAPHORIN; TOLL LIKE RECEPTOR 4; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR T BET; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VASCULOTROPIN;

ADAPTIVE IMMUNITY; APOPTOSIS; ARTICLE; CANCER GROWTH; CANCER PROGNOSIS; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL INFILTRATION; COLORECTAL CANCER; DENDRITIC CELL; GENE MUTATION; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; MACROPHAGE; METASTASIS; NEUTROPHIL; NONHUMAN; PROTEIN EXPRESSION; SURVIVAL; TUMOR REJECTION;

EID: 84873627270     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v19.i2.174     Document Type: Article

References (88)

1. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010; 15: 699-731 [PMID: 20584808 DOI: 10.1634/theoncologist.2010-0025]
2. Michor F, Iwasa Y, Lengauer C, Nowak MA. Dynamics of colorectal cancer. Semin Cancer Biol 2005; 15: 484-493 [PMID: 16055342 DOI: 10.1016/j.semcancer.2005.06.005]
3. Jass JR. Colorectal cancer: a multipathway disease. Crit Rev Oncog 2006; 12: 273-287 [PMID: 17425506]
4. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-767 [PMID: 2188735 DOI: 10.1016/0092-8674(90)90186-I]
5. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525-532 [PMID: 2841597 DOI: 10.1056/NEJM198809013190901]
6. Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2011; 60: 397-411 [PMID: 21036793 DOI: 10.1136/gut.2010.217182]
7. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010; 138: 2059-2072 [PMID: 20420946 DOI: 10.1053/j.gastro.2009.12.065]
8. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138: 2073-2087.e3 [PMID: 20420947 DOI: 10.1053/j.gastro.2009.12.064]
9. Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 2008; 29: 673-680 [PMID: 17942460 DOI: 10.1093/carcin/bgm228]
10. Hyde A, Fontaine D, Stuckless S, Green R, Pollett A, Simms M, Sipahimalani P, Parfrey P, Younghusband B. A histologybased model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol 2010; 34: 1820-1829 [PMID: 21107088 DOI: 10.1097/PAS.0b013e3181f6a912]
11. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58: 5248-5257 [PMID: 9823339]
12. Malesci A, Laghi L, Bianchi P, Delconte G, Randolph A, Torri V, Carnaghi C, Doci R, Rosati R, Montorsi M, Roncalli M, Gennari L, Santoro A. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 2007; 13: 3831-3839 [PMID: 17606714 DOI: 10.1158/1078-0432.CCR-07-0366]
13. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000; 342: 69-77 [PMID: 10631274 DOI: 10.1056/NEJM200001133420201]
14. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004; 126: 394-401 [PMID: 14762775 DOI: 10.1053/ j.gastro.2003.12.023]
15. McLean MH, Murray GI, Stewart KN, Norrie G, Mayer C, Hold GL, Thomson J, Fyfe N, Hope M, Mowat NA, Drew JE, El-Omar EM. The inflammatory microenvironment in colorectal neoplasia. PLoS One 2011; 6: e15366 [PMID: 21249124 DOI: 10.1371/journal.pone.0015366]
16. Peddareddigari VG, Wang D, Dubois RN. The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron 2010; 3: 149-166 [PMID: 21209781 DOI: 10.1007/ s12307-010-0038-3]
17. Halama N, Michel S, Kloor M, Zoernig I, Pommerencke T, von Knebel Doeberitz M, Schirmacher P, Weitz J, Grabe N, Jäger D. The localization and density of immune cells in primary tumors of human metastatic colorectal cancer shows an association with response to chemotherapy. Cancer Immun 2009; 9: 1 [PMID: 19226101]
18. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313: 1960-1964 [PMID: 17008531 DOI: 10.1126/science.1129139]
19. Galon J, Fridman WH, Pagès F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 2007; 67: 1883-1886 [PMID: 17332313 DOI: 10.1158/0008-5472.CAN-06-4806]
20. Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28: 4531-4538 [PMID: 20516428 DOI: 10.1200/JCO.2009.27.2146]
21. Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet 2008; 371: 771-783 [PMID: 18275997 DOI: 10.1016/S0140-6736(08)60241-X]
22. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454: 436-444 [PMID: 18650914 DOI: 10.1038/nature07205]
23. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001; 1: 46-54 [PMID: 11900251 DOI:10.1038/35094059]
24. Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004; 4: 839-849 [PMID: 15516957 DOI: 10.1038/nrc1477]
25. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432: 332-337 [PMID: 15549095 DOI: 10.1038/nature03096]
26. Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J Clin Oncol 2010; 28: 4045-4051 [PMID: 20644090 DOI: 10.1200/JCO.2010.27.9992]
27. Saleh M, Trinchieri G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol 2011; 11: 9-20 [PMID: 21151034 DOI: 10.1038/nri2891]
28. Salama P, Platell C. Host response to colorectal cancer. ANZ J Surg 2008; 78: 745-753 [PMID: 18844901 DOI: 10.1111/j.1445-2197.2008.04642.x]
29. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11: 889-896 [PMID: 20856220 DOI: 10.1038/ni.1937]
30. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010; 22: 231-237 [PMID: 20144856 DOI: 10.1016/j.coi.2010.01.009]
31. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A. Macrophage polarization in tumour progression. Semin Cancer Biol 2008; 18: 349-355 [PMID: 18467122 DOI: 10.1016/j.semcancer.2008.03.004]
32. Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 2006; 177: 7303-7311 [PMID:17082649]
33. Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. Eur J Immunol 2007; 37: 14-16 [PMID: 17183610 DOI: 10.1002/eji.200636910]
34. Rigo A, Gottardi M, Zamò A, Mauri P, Bonifacio M, KramperaM, Damiani E, Pizzolo G, Vinante F. Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. Mol Cancer 2010; 9: 273 [PMID: 20946648 DOI: 10.1186/1476-4598-9-273].]
35. Kang JC, Chen JS, Lee CH, Chang JJ, Shieh YS. Intratumoral macrophage counts correlate with tumor progression in colorectal cancer. J Surg Oncol 2010; 102: 242-248 [PMID: 20740582 DOI: 10.1002/jso.21617]
36. Papadopoulou S, Scorilas A, Arnogianaki N, Papapanayiotou B, Tzimogiani A, Agnantis N, Talieri M. Expression of gelatinase-A (MMP-2) in human colon cancer and normal colon mucosa. Tumour Biol 2001; 22: 383-389 [PMID: 11786732 DOI: 10.1159/000050641]
37. Herszényi L, Sipos F, Galamb O, Solymosi N, Hritz I, Miheller P, Berczi L, Molnár B, Tulassay Z. Matrix metalloproteinase- 9 expression in the normal mucosa-adenoma-dysplasiaadenocarcinoma sequence of the colon. Pathol Oncol Res 2008; 14: 31-37 [PMID: 18347934 DOI: 10.1007/s12253-008-9004-5]
38. Kaler P, Galea V, Augenlicht L, Klampfer L. Tumor associated macrophages protect colon cancer cells from TRAILinduced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells. PLoS One 2010; 5: e11700 [PMID: 20661477 DOI: 10.1371/journal.pone.0011700]
39. Li YY, Hsieh LL, Tang RP, Liao SK, Yeh KY. Interleukin-6 (IL-6) released by macrophages induces IL-6 secretion in the human colon cancer HT-29 cell line. Hum Immunol 2009; 70: 151-158 [PMID: 19272324 DOI: 10.1016/j.humimm.2009.01.004]
40. Herbeuval JP, Lelievre E, Lambert C, Dy M, Genin C. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol 2004; 172: 4630-4636 [PMID: 15034082]
41. Li YY, Chang JW, Hsieh LL, Yeh KY. Neutralization of interleukin (IL)-10 released by monocytes/macrophages enhances the up-regulatory effect of monocyte/macrophage-derived IL-6 on expressions of IL-6 and MUC1, and migration in HT-29 colon cancer cells. Cell Immunol 2010; 265: 164-171 [PMID: 20851386 DOI: 10.1016/j.cellimm.2010.07.014]
42. Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 2005; 167: 627-635 [PMID: 16127144 DOI: 10.1016/S0002-9440(10)62038-X]
43. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 2006; 25: 315-322 [PMID: 16967326 DOI: 10.1007/s10555-006-9001-7]
44. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 2007; 13: 1472-1479 [PMID: 17332291 DOI: 10.1158/1078-0432.CCR-06-2073]
45. Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM, Zhang X, Pang ZZ, Wan DS, Zeng YX, Zhang XS. The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med 2010; 8: 13 [PMID: 20141634 DOI: 10.1186/1479-5876-8-13]
46. Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T, Takami T. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 2008; 83: 1136-1144 [PMID: 18285406 DOI: 10.1189/jlb.0907611]
47. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 2009; 16: 91-102 [PMID: 19647220 DOI: 10.1016/j.ccr.2009.06.018]
48. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, van Krieken JH. Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect--a histopathological and immunohistochemical study. BMC Cancer 2001; 1: 7 [PMID: 11481031 DOI: 10.1186/1471-2407-1-7]
49. Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T, Weissleder R, McNagny KM, Khazaie K. Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA 2007; 104: 19977-19982 [PMID: 18077429 DOI: 10.1073/pnas.0704620104]
50. Nielsen HJ, Hansen U, Christensen IJ, Reimert CM, Brünner N, Moesgaard F. Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J Pathol 1999; 189: 487-495 [PMID: 10629548 DOI: 10.1002/(SICI)1096 -9896(199912)189: ]
51. Gulubova M, Vlaykova T. Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 2009; 24: 1265-1275 [PMID: 17645466 DOI: 10.1111/ j.1440-1746.2007.05009.x]
52. Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, Weitz J, Koch M, Halverson AL, Bentrem DJ, Khazaie K. In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci USA 2010; 107: 6430-6435 [PMID: 20308560 DOI: 10.1073/pnas.0913683107]
53. Halazun KJ, Aldoori A, Malik HZ, Al-Mukhtar A, Prasad KR, Toogood GJ, Lodge JP. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol 2008; 34: 55-60 [PMID: 17448623 DOI: 10.1016/j.ejso.2007.02.014]
54. Vesely P, Tousková M, Melichar B. Phenotype of peripheral blood leukocytes and survival of patients with metastatic colorectal cancer. Int J Biol Markers 2005; 20: 126-133 [PMID: 16011044]
55. Holcombe RF, Jacobson J, Dakhil SR, Stewart RM, Betzing KS, Kannan K, Macdonald JS. Association of immune parameters with clinical outcome in stage III colon cancer: results of Southwest Oncology Group Protocol 9009. CancerImmunol Immunother 1999; 48: 533-539 [PMID: 10602891 DOI: 10.1007/s002620050602]
56. Xie ZJ, Jia LM, He YC, Gao JT. Morphological observation of tumor infiltrating immunocytes in human rectal cancer. World J Gastroenterol 2006; 12: 1757-1760 [PMID: 16586547]
57. Suzuki A, Masuda A, Nagata H, Kameoka S, Kikawada Y, Yamakawa M, Kasajima T. Mature dendritic cells make clusters with T cells in the invasive margin of colorectal carcinoma. J Pathol 2002; 196: 37-43 [PMID: 11748640 DOI:10.1002/path.1018]
58. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801 [PMID: 16497588 DOI: 10.1016/j.cell.2006.02.015]
59. Franchi L, McDonald C, Kanneganti TD, Amer A, Núñez G. Nucleotide-binding oligomerization domain-like receptors: intracellular pattern recognition molecules for pathogen detection and host defense. J Immunol 2006; 177: 3507-3513 [PMID: 16951308]
60. Fukata M, Hernandez Y, Conduah D, Cohen J, Chen A, Breglio K, Goo T, Hsu D, Xu R, Abreu MT. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm Bowel Dis 2009; 15: 997-1006 [PMID: 19229991 DOI:10.1002/ibd.20880]
61. Chen GY, Shaw MH, Redondo G, Núñez G. The innate immune receptor Nod1 protects the intestine from inflammation- induced tumorigenesis. Cancer Res 2008; 68: 10060-10067 [PMID: 19074871 DOI: 0008-5472.CAN-08-2061]
62. Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology 2010; 138: 2101-2114.e5 [PMID: 20420949 DOI: 10.1053/j.gastro.2010.01.058]
63. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, Satomi S. 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 2004; 91: 1711-1717 [PMID: 15494715]
64. Banerjea A, Bustin SA, Dorudi S. The immunogenicity of colorectal cancers with high-degree microsatellite instability. World J Surg Oncol 2005; 3: 26 [PMID: 15890075 DOI: 10.1186/1477-7819-3-26]
65. Paschen A, Eichmuller S, Schadendorf D. Identification of tumor antigens and T-cell epitopes, and its clinical application. Cancer Immunol Immunother 2004; 53: 196-203 [PMID: 14689239 DOI: 10.1007/s00262-003-0479-3]
66. Loose D, Van de Wiele C. The immune system and cancer. Cancer Biother Radiopharm 2009; 24: 369-376 [PMID: 19538060 DOI: 10.1089/cbr.2008.0593]
67. Barnas JL, Simpson-Abelson MR, Yokota SJ, Kelleher RJ, Bankert RB. T cells and stromal fibroblasts in human tumor microenvironments represent potential therapeutic targets. Cancer Microenviron 2010; 3: 29-47 [PMID: 21209773 DOI: 10.1007/s12307-010-0044-5]
68. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6: 295-307 [PMID: 16557261 DOI: 10.1038/nri1806]
69. Saurer L, Mueller C. T cell-mediated immunoregulation in the gastrointestinal tract. Allergy 2009; 64: 505-519 [PMID: 19210347 DOI: 10.1111/j.1398-9995.2009.01965.x]
70. Needham DJ, Lee JX, Beilharz MW. Intra-tumoural regulatory T cells: a potential new target in cancer immunotherapy. Biochem Biophys Res Commun 2006; 343: 684-691 [PMID: 16563349 DOI: 10.1016/j.bbrc.2006.03.018]
71. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 2006; 1: e129 [PMID: 17205133 DOI: 10.1371/journal.pone.0000129]
72. Khan AR, Dovedi SJ, Wilkinson RW, Pritchard DI. Tumor infiltrating regulatory T cells: tractable targets for immunotherapy. Int Rev Immunol 2010; 29: 461-484 [PMID: 20839911 DOI: 10.3109/08830185.2010.508854]
73. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942-949 [PMID: 15322536 DOI: 10.1038/nm1093]
74. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006; 12: 5423-5434 [PMID: 17000676 DOI: 10.1158/1078-0432.CCR-06-0369]
75. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, Nakajima A, Hirohashi S. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 2007; 13: 902-911 [PMID: 17289884 DOI: 10.1158/1078-0432.CCR-06-2363]
76. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27: 186-192 [PMID: 19064967 DOI: 10.1200/JCO.2008.18.7229]
77. 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. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010; 33: 435-441 [PMID: 20386463 DOI: 10.1097/CJI.0b013e3181d32f01]
78. Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, Sozaki M, Tanaka M, Onishi H, Morisaki T, Katano M. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010; 59: 653-661 [PMID: 19908042 DOI: 10.1007/s00262-009-0781-9]
79. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 2010; 126: 2635-2643 [PMID: 19856313]
80. Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès- Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 2010; 29: 1093-1102 [PMID: 19946335 DOI: 10.1038/ onc.2009.416]
81. Zlobec I, Lugli A. Invasive front of colorectal cancer: dynamic interface of pro-/anti-tumor factors. World J Gastro enterol 2009; 15: 5898-5906 [PMID: 20014453 DOI: 10.3748/wjg.15.5898]
82. Pagès 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 PH, Trajanoski Z, Fridman WH, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353: 2654-2666 [PMID: 16371631 DOI: 10.1056/NEJMoa051424]
83. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, Vermorken JB. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 2010; 11: 19 [PMID: 20385003 DOI: 10.1186/1471-2172-11-19]
84. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329-360 [PMID: 15032581 DOI: 10.1146/annurev.immunol.22.012703.104803]
85. 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. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol 2009; 10: 877-884 [PMID: 19656725 DOI: 10.1016/S1470-2045(09)70186-X]
86. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222: 350-366 [PMID: 20927778 DOI:10.1002/path.2774]
87. Grizzi F, Chiriva-Internati M. Cancer: looking for simplicity and finding complexity. Cancer Cell Int 2006; 6: 4 [PMID: 16480511 DOI: 10.1186/1475-2867-6-4]
88. Grizzi F, Di Ieva A, Russo C, Frezza EE, Cobos E, Muzzio PC, Chiriva-Internati M. Cancer initiation and progression: an unsimplifiable complexity. Theor Biol Med Model 2006; 3: 37 [PMID: 17044918 DOI: 10.1186/1742-4682-3-37]