The cellular ratio of immune tolerance (immunoCRIT) is a definite marker for aggressiveness of solid tumors and may explain tumor dissemination patterns

References

• Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22:329 - 60; http://dx.doi.org/10.1146/annurev.immunol.22.012703.104803; PMID: 15032581
   PubMed Web of Science ®Google Scholar
• Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3:991 - 8; http://dx.doi.org/10.1038/ni1102-991; PMID: 12407406
   PubMed Web of Science ®Google Scholar
• Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest 2007; 117:1167 - 74; http://dx.doi.org/10.1172/JCI31202; PMID: 17476346
   PubMed Web of Science ®Google Scholar
• Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol 2008; 20:241 - 6; http://dx.doi.org/10.1016/j.coi.2008.04.008; PMID: 18508251
   PubMed Web of Science ®Google Scholar
• Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531 - 62; http://dx.doi.org/10.1146/annurev.immunol.21.120601.141122; PMID: 15032588
   PubMed Web of Science ®Google Scholar
• Khattri R, Cox T, Yasayko S-A, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4:337 - 42; http://dx.doi.org/10.1038/ni909; PMID: 12612581
   PubMed Web of Science ®Google Scholar
• Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330 - 6; http://dx.doi.org/10.1038/ni904; PMID: 12612578
   PubMed Web of Science ®Google Scholar
• Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005; 22:329 - 41; http://dx.doi.org/10.1016/j.immuni.2005.01.016; PMID: 15780990
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057 - 61; http://dx.doi.org/10.1126/science.1079490; PMID: 12522256
   PubMed Web of Science ®Google Scholar
• Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007; 13:108 - 16; http://dx.doi.org/10.1016/j.molmed.2007.01.003; PMID: 17257897
   PubMed Web of Science ®Google Scholar
• Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 2005; 92:913 - 20; http://dx.doi.org/10.1038/sj.bjc.6602407; PMID: 15714205
   PubMed Web of Science ®Google Scholar
• Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005; 65:2457 - 64; http://dx.doi.org/10.1158/0008-5472.CAN-04-3232; PMID: 15781662
   PubMed Web of Science ®Google Scholar
• Liyanage UK, Moore TT, Joo H-G, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002; 169:2756 - 61; PMID: 12193750
   PubMed Web of Science ®Google Scholar
• Gray CP, Arosio P, Hersey P. Association of increased levels of heavy-chain ferritin with increased CD4+ CD25+ regulatory T-cell levels in patients with melanoma. Clin Cancer Res 2003; 9:2551 - 9; PMID: 12855630
   PubMed Web of Science ®Google Scholar
• Viguier M, Lemaître F, Verola O, Cho M-S, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 2004; 173:1444 - 53; PMID: 15240741
   PubMed Web of Science ®Google Scholar
• Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 2003; 98:1089 - 99; http://dx.doi.org/10.1002/cncr.11618; PMID: 12942579
   PubMed Web of Science ®Google Scholar
• Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 2003; 9:4404 - 8; PMID: 14555512
   PubMed Web of Science ®Google Scholar
• Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Fujii H. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 2006; 55:1064 - 71; http://dx.doi.org/10.1007/s00262-005-0092-8; PMID: 16328385
   PubMed Web of Science ®Google Scholar
• Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E, Deibl M, Gastl G, Gunsilius E, Marth C. The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005; 11:8326 - 31; http://dx.doi.org/10.1158/1078-0432.CCR-05-1244; PMID: 16322292
   PubMed Web of Science ®Google Scholar
• Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942 - 9; http://dx.doi.org/10.1038/nm1093; PMID: 15322536
   PubMed Web of Science ®Google Scholar
• Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313:1960 - 4; http://dx.doi.org/10.1126/science.1129139; PMID: 17008531
   PubMed Web of Science ®Google Scholar
• Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006; 24:5373 - 80; http://dx.doi.org/10.1200/JCO.2006.05.9584; PMID: 17135638
   PubMed Web of Science ®Google Scholar
• Keino H, Takeuchi M, Kezuka T, Hattori T, Usui M, Taguchi O, et al. Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Investigative Ophthalmology &amp. Visual Science 2006; 47:1047 - 55
   Google Scholar
• McPherson SW, Heuss ND, Gregerson DS. Regulation of CD8(+) T Cell Responses to Retinal Antigen by Local FoxP3(+) Regulatory T Cells. Front Immunol 2012; 3:166; http://dx.doi.org/10.3389/fimmu.2012.00166; PMID: 22737153
   PubMedGoogle Scholar
• Cervantes-Barragán L, Firner S, Bechmann I, Waisman A, Lahl K, Sparwasser T, Thiel V, Ludewig B. Regulatory T cells selectively preserve immune privilege of self-antigens during viral central nervous system infection. J Immunol 2012; 188:3678 - 85; http://dx.doi.org/10.4049/jimmunol.1102422; PMID: 22407917
   PubMed Web of Science ®Google Scholar
• Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol 2008; 3:221 - 47; http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.151523; PMID: 18233952
   PubMed Web of Science ®Google Scholar
• Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94:2698 - 705; http://dx.doi.org/10.1002/cncr.10541; PMID: 12173339
   PubMed Web of Science ®Google Scholar
• Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004; 350:1655 - 64; http://dx.doi.org/10.1056/NEJMra030831; PMID: 15084698
   PubMed Web of Science ®Google Scholar
• Sehouli J, Pietzner K, Harter P, Münstedt K, Mahner S, Hasenburg A, Camara O, Wimberger P, Boehmer D, Buehling KJ, et al. Prognostic role of platinum sensitivity in patients with brain metastases from ovarian cancer: results of a German multicenter study. Ann Oncol 2010; 21:2201 - 5; http://dx.doi.org/10.1093/annonc/mdq229; PMID: 20439341
   PubMed Web of Science ®Google Scholar
• Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. SEER Cancer Statistics Review, 1975-2008. National Cancer Institute, 2008.
   Google Scholar
• Kolles H, Stegmaier C, von Seebach HB, Ziegler H. Deskriptive Epidemiologie und Prognose maligner gynäkologischer Tumoren. Geburtshilfe Frauenheilkd 1989; 49:573 - 8; http://dx.doi.org/10.1055/s-2008-1035842; PMID: 2787260
   PubMed Web of Science ®Google Scholar
• Hart WR. Borderline epithelial tumors of the ovary. Mod Pathol 2005; 18:Suppl 2 S33 - 50; http://dx.doi.org/10.1038/modpathol.3800307; PMID: 15761465
   PubMed Web of Science ®Google Scholar
• Kaern J, Tropé CG, Kristensen GB, Abeler VM, Pettersen EO. DNA ploidy; the most important prognostic factor in patients with borderline tumors of the ovary. Int J Gynecol Cancer 1993; 3:349 - 58; http://dx.doi.org/10.1046/j.1525-1438.1993.03060349.x; PMID: 11578368
   PubMed Web of Science ®Google Scholar
• Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007; 5:e38 - , e; http://dx.doi.org/10.1371/journal.pbio.0050038; PMID: 17298177
   PubMed Web of Science ®Google Scholar
• Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res 2009; 69:599 - 608; http://dx.doi.org/10.1158/0008-5472.CAN-08-2361; PMID: 19147574
   PubMed Web of Science ®Google Scholar
• Baron U, Floess S, Wieczorek G, Baumann K, Grützkau A, Dong J, Thiel A, Boeld TJ, Hoffmann P, Edinger M, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007; 37:2378 - 89; http://dx.doi.org/10.1002/eji.200737594; PMID: 17694575
   PubMed Web of Science ®Google Scholar
• Sehouli J, Loddenkemper C, Cornu T, Schwachula T, Hoffmüller U, Grützkau A, Lohneis P, Dickhaus T, Gröne J, Kruschewski M, et al. Epigenetic quantification of tumor-infiltrating T-lymphocytes. Epigenetics 2011; 6:236 - 46; http://dx.doi.org/10.4161/epi.6.2.13755; PMID: 20962591
   PubMed Web of Science ®Google Scholar
• Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993; 39:561 - 77; PMID: 8472349
   PubMed Web of Science ®Google Scholar
• Jonckheere AR. A test of significance for the relation between m rankings and k ranked categories. Br J Stat Psychol 1954; 7:93 - 100; http://dx.doi.org/10.1111/j.2044-8317.1954.tb00148.x
   Web of Science ®Google Scholar
• Page EB. Ordered hypotheses for multiple treatments: a significance test for linear ranks. J Am Stat Assoc 1963; 58:216 - 30; http://dx.doi.org/10.1080/01621459.1963.10500843
   Web of Science ®Google Scholar
• Chekerov R, Koensgen D, Klaman I, Rosenthal A, Oskay-Oezcelik G, Mustea A, et al. Tumor- and stromal cell-specific expression of topoisomerase IIa and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study. Mol Med Report 2009; 2:1011 - 6; http://dx.doi.org/10.3892/mmr_00000207
   Web of Science ®Google Scholar
• Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, Vermorken JB, Torri V, Mangioni C, Pecorelli S, et al, International Collaborative Ovarian Neoplasm 1, European Organisation for Research and Treatment of Cancer Collaborators-Adjuvant ChemoTherapy un Ovarian Neoplasm. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003; 95:105 - 12; http://dx.doi.org/10.1093/jnci/95.2.113; PMID: 12529343
   PubMed Web of Science ®Google Scholar
• Aust S, Bachmayr-Heyda A, Pateisky P, Tong D, Darb-Esfahani S, Denkert C, Chekerov R, Sehouli J, Mahner S, Van Gorp T, et al. Role of TRAP1 and estrogen receptor alpha in patients with ovarian cancer -a study of the OVCAD consortium. Mol Cancer 2012; 11:69; http://dx.doi.org/10.1186/1476-4598-11-69; PMID: 22978347
   PubMed Web of Science ®Google Scholar
• Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, Kenny SL, Kay E, Hodgkinson E, Pope M, et al, MRC COIN Trial Investigators. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol 2011; 12:642 - 53; http://dx.doi.org/10.1016/S1470-2045(11)70102-4; PMID: 21641867
   PubMed Web of Science ®Google Scholar
• Streiner DL. The case of the missing data: methods of dealing with dropouts and other research vagaries. Can J Psychiatry 2002; 47:68 - 75; PMID: 11873711
   PubMed Web of Science ®Google Scholar