• 1
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol 2002; 3:991998.
  • 2
    Quezada SA, Peggs KS, Simpson TR, Allison JP. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication. Immunol Rev 2011; 241:104118.
  • 3
    Schreiber TH, Podack ER. A critical analysis of the tumour immunosurveillance controversy for 3-MCA- induced sarcomas. Br J Cancer 2009; 101:381386.
  • 4
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:15651570.
  • 5
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646674.
  • 6
    Betts G, Jones E, Junaid S et al. Suppression of tumour-specific CD4+ T cells by regulatory T cells is associated with progression of human colorectal cancer. Gut 2012; 61:11631171.
  • 7
    Koebel CM, Vermi W, Swann JB et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450:903924.
  • 8
    Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437:141146.
  • 9
    Radoja S, Rao TD, Hillman D, Frey AB. Mice bearing late-stage tumors have normal functional systemic T cell responses in vitro and in vivo. J Immunol 2000; 164:26192628.
  • 10
    Kurt RA, Park JA, Panelli MC et al. T-lymphocytes infiltrating sites of tumor rejection and progression display identical V-beta usage but different cytotoxic activities. J Immunol 1995; 154:39693974.
  • 11
    Kurt RA, Park JA, Schluter SF, Marchalonis JJ, Akporiaye ET. TCR V-beta usage and clonality of T cells isolated from progressing and rejected tumor sites before and after in vitro culture. Int Immunol 2000; 12:639646.
  • 12
    Zou WP. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6:295307.
  • 13
    Menetrier-Caux C, Curiel T, Faget J, Manuel M, Caux C, Zou W. Targeting regulatory T cells. Target Oncol 2012; 7:1528.
  • 14
    Zhou G, Levitsky HI. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 2007; 178:21552162.
  • 15
    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; 65:24572464.
  • 16
    Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011; 60:909918.
  • 17
    Nizar S, Copier J, Meyer B et al. T-regulatory cell modulation: the future of cancer immunotherapy? Br J Cancer 2009; 100:16971703.
  • 18
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunological self-tolerance maintained by activated T-cells expressing Il-2 receptor alpha-chains (Cd25) – breakdown of a single mechanism of self-tolerance causes various autoimmune-diseases. J Immunol 1995; 155:11511164.
  • 19
    Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol 2011; 23:424430.
  • 20
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 2003; 4:330336.
  • 21
    Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3(+) T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009; 106:19031908.
  • 22
    Zhou XY, Bailey-Bucktrout SL, Jeker LT et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009; 10:10001104.
  • 23
    Rubtsov YP, Niec RE, Josefowicz S et al. Stability of the regulatory T cell lineage in vivo. Science 2010; 329:16671671.
  • 24
    Gavin MA, Torgerson TR, Houston E et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 2006; 103:66596664.
  • 25
    Miyara M, Yoshioka Y, Kitoh A et al. Functional delineation and differentiation dynamics of human CD4(+) T cells expressing the FoxP3 transcription factor. Immunity 2009; 30:899911.
  • 26
    Miyao T, Floess S, Setoguchi R et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012; 36:262275.
  • 27
    Elkord E, Sharma S, Burt DJ, Hawkins RE. Expanded subpopulation of FoxP3(+) T regulatory cells in renal cell carcinoma co-express Helios, indicating they could be derived from natural but not induced Tregs. Clin Immunol 2011; 140:218222.
  • 28
    Getnet D, Grosso JF, Goldberg MV et al. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol Immunol 2010; 47:15951600.
  • 29
    Thornton AM, Korty PE, Tran DQ et al. Expression of helios, an ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3(+) T regulatory cells. J Immunol 2010; 184:34333441.
  • 30
    Curiel TJ, Coukos G, Zou LH et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942949.
  • 31
    Gobert M, Treilleux I, Bendriss-Vermare N et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 2009; 69:20002009.
  • 32
    Ishida T, Ishii T, Inagaki A et al. Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 2006; 66:57165722.
  • 33
    Iellem A, Mariani M, Lang R et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 2001; 194:847853.
  • 34
    Sutmuller RPM, van Duivenvoorde LM, van Elsas A et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194:823832.
  • 35
    Mizukami Y, Kono K, Kawaguchi Y et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3(+) regulatory T cells in gastric cancer. Int J Cancer 2008; 122:22862293.
  • 36
    Maruyama T, Kono K, Izawa S et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Dis Esophagus 2010; 23:422429.
  • 37
    Facciabene A, Peng XH, Hagemann IS et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475:226U141.
  • 38
    Tan MCB, Goedegebuure PS, Belt BA et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 2009; 182:17461755.
  • 39
    Ahmadzadeh M, Rosenberg ST. IL-2 administration increases CD4(+)CD25(hi) Foxp3(+) regulatory T cells in cancer patients. Blood 2006; 107:24092414.
  • 40
    Jensen HK, Donskov F, Nordsmark M, Marcussen N, von der Maase H. Increased Intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. Clin Cancer Res 2009; 15:10521058.
  • 41
    Ghiringhelli F, Puig PE, Roux S et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4(+)CD25(+) regulatory T cell proliferation. J Exp Med 2005; 202:919929.
  • 42
    Chen WJ, Jin WW, Hardegen N et al. Conversion of peripheral CD4(+)CD25(–) naive T cells to CD4(+)CD25(+) regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198:18751886.
  • 43
    Liu VC, Wong LY, Jang T et al. Tumor evasion of the immune system by converting CD4(+) CD25(–) T cells into CD4(+) CD25(+) T regulatory cells: role of tumor-derived TGF-beta. J Immunol 2007; 178:28832892.
  • 44
    Curti A, Pandolfi S, Valzasina B et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25(–) into CD25(+) T regulatory cells. Blood 2007; 109:28712877.
  • 45
    Sharma MD, Baban B, Chandler P et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 2007; 117:25702582.
  • 46
    Hindley JP, Ferreira C, Jones E et al. Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 2011; 71:736746.
  • 47
    Bui JD, Uppaluri R, Hsieh CS, Schreiber RD. Comparative analysis of regulatory and effector T cells in progressively growing versus rejecting tumors of similar origins. Cancer Res 2006; 66:73017309.
  • 48
    Valzasina B, Piconese S, Guiducci C, Colombo MP. Tumor-induced expansion of regulatory T cells by conversion of CD4(+)CD25(–) lymphocytes is thymus and proliferation independent. Cancer Res 2006; 66:44884495.
  • 49
    Greene MI, Fujimoto S, Sehon AH. Nature of immunosuppressor T cells and their factors in tumor-bearing host (Tbh). J Immunol 1976; 116:791806.
  • 50
    Clemente CG, Mihm MG, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996; 77:13031310.
  • 51
    Sato E, Olson SH, Ahn J et al. Intraepithelial CD8(+) tumor-infiltrating lymphocytes and a high CD8(+)/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102:1853818543.
  • 52
    Galon J, Costes A, Sanchez-Cabo F et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 313:19601964.
  • 53
    Bates GJ, Fox SB, Han C et al. 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; 24:53735380.
  • 54
    Petersen RP, Carnpa MJ, Sperlazza J et al. Tumor infiltrating FOXP3(+) regulatory T-cells are associated with recurrence in pathologic stage INSCLC patients. Cancer 2006; 107:28662872.
  • 55
    Gao Q, Qiu SJ, Fan J et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:25862593.
  • 56
    Griffiths RW, Elkord E, Gilham DE et al. Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 2007; 56:17431753.
  • 57
    Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3(+) regulatory T cells increases during the progression of pancreatic ductal adenocarcinorna and its premalignant lesions. Clin Cancer Res 2006; 12:54235434.
  • 58
    Perrone G, Ruffini PA, Catalano V et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 2008; 44:18751882.
  • 59
    Jordanova ES, Gorter A, Ayachi O et al. Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8(+)/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin Cancer Res 2008; 14:20282035.
  • 60
    Antony PA, Piccirillo CA, Akpinarli A et al. CD8+T cell immunity against a tumor/self-antigen is augmented by CD4(+) T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 2005; 174:25912601.
  • 61
    Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 2004; 200:771782.
  • 62
    Salama P, Phillips M, Grieu F et al. Tumor-infiltrating FOXP3(+) T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27:186192.
  • 63
    Nosho K, Baba Y, Tanaka N et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222:350366.
  • 64
    Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3(+) regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 2008; 93:193200.
  • 65
    Badoual C, Hans S, Rodriguez J et al. Prognostic value of tumor-infiltrating CD4(+) T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12:465472.
  • 66
    Zhang YL, Li J, Mo HY et al. Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways. Mol Cancer 2010; 9:415.
  • 67
    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30:10731081.
  • 68
    Pellegatta S, Cuppini L, Finocchiaro G. Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas. Exp Rev Anticancer Ther 2011; 11:17591774.
  • 69
    Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25(+)CD4(+) T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163:52115218.
  • 70
    Golgher D, Jones E, Powrie F, Elliott T, Gallimore A. Depletion of CD25(+) regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 2002; 32:32673275.
  • 71
    Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59:31283133.
  • 72
    Comes A, Rosso O, Orengo AM et al. CD25(+) regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. J Immunol 2006; 176:17501758.
  • 73
    Prasad SJ, Farrand KJ, Matthews SA, Chang JH, McHugh RS, Ronchese F. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4(+)CD25(+) regulatory T cells. J Immunol 2005; 174:9098.
  • 74
    Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Cancer Vaccines 2009; 1174:99106.
  • 75
    Talpur R, Jones DM, Alencar AJ et al. CD25 expression is correlated with histological grade and response to denileukin diftitox in cutaneous T-cell lymphoma. J Invest Dermatol 2006; 126:575583.
  • 76
    Dannull J, Su Z, Rizzieri D et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005; 115:36233633.
  • 77
    Gerena-Lewis M, Crawford J, Bonomi P et al. A phase II trial of denileukin diftitox in patients with previously treated advanced non-small cell lung cancer. Am J Clin Oncol Cancer Clin Trials 2009; 32:269273.
  • 78
    Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB(389)IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 2005; 28:582592.
  • 79
    Powell DJ, Felipe-Silva A, Merino MJ et al. Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J Immunol 2007; 179:49194928.
  • 80
    Yoshida S, Nomoto K, Himeno K, Takeya K. Immune-response to syngeneic or autologous testicular cells in mice. 1. Augmented delayed footpad reaction in cyclophosphamide-treated mice. Clin Exp Immunol 1979; 38:211217.
  • 81
    Ghiringhelli F, Larmonier N, Schmitt E et al. CD4(+)CD25(+) regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004; 34:336344.
  • 82
    Berd D, Mastrangelo MJ. Effect of low-dose cyclophosphamide on the immune system of cancer patients – depletion of Cd4+, 2H4+ suppressor-inducer T-cells. Cancer Res 1988; 48:16711675.
  • 83
    MacLean GD, Miles DW, Rubens RD, Reddish MA, Longenecker BM. Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunother 1996; 19:309316.
  • 84
    Ghiringhelli F, Menard C, Puig PE et al. Metronomic cyclophosphamide regimen selectively depletes CD4(+) CD25(+) regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007; 56:641648.
  • 85
    Lord R, Nair S, Schache A et al. Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol 2007; 177:21362140.
  • 86
    Lutsiak MEC, Semnani RT, De Pascalis R, Kashmiri SVS, Schlom J, Sabzevari H. Inhibition of CD4(+)25(+) T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005; 105:28622868.
  • 87
    Audia S, Nicolas A, Cathelin D et al. Increase of CD4(+)CD25(+) regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4(+)CD25(+) T lymphocytes. Clin Exp Immunol 2007; 150:523530.
  • 88
    Chen CA, Ho CM, Chang MC et al. Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis. Mol Ther 2010; 18:12331243.
  • 89
    Eralp Y, Wang X, Wang JP, Maughan MF, Polo JM, Lachman LB. Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER-2/neu in a murine mammary carcinoma model. Breast Cancer Res Treat 2004; 88:S246S247.
  • 90
    Zhang L, Dermawan K, Jin ML et al. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 2008; 129:219229.
  • 91
    Laurie KL, Van Driel IR, Gleeson PA. Role of CD4(+)CD25(+) immunoregulatory T cells in the induction of autoimmune gastritis. Immunol Cell Biol 2002; 80:567573.
  • 92
    Powell DJ, de Vries CR, Allen T, Ahmadzadeh M, Rosenberg SA. Inability to mediate prolonged reduction of regulatory T cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy. J Immunother 2007; 30:438447.
  • 93
    Thistlethwaite FC, Elkord E, Griffiths RW et al. Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother 2008; 57:623634.
  • 94
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271:17341736.
  • 95
    Kwon ED, Foster BA, Hurwitz AA et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc Natl Acad Sci USA 1999; 96:1507415079.
  • 96
    Hurwitz AA, Foster BA, Kwon ED et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 2000; 60:24442448.
  • 97
    Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med 2010; 363:711723.
  • 98
    Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005; 175:77467754.
  • 99
    O'Mahony D, Janik JE. Comment on ‘analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade’. J Immunol 2006; 176:5136.
  • 100
    Kim JD, Choi BK, Bae JS et al. Cloning and characterization of GITR ligand. Genes Immun 2003; 4:564569.
  • 101
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+CD4+regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3:135142.
  • 102
    Ko K, Yamazaki S, Nakamura K et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3(+)CD25(+)CD4(+) regulatory T cells. J Exp Med 2005; 202:885891.
  • 103
    Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006; 116:19351945.
  • 104
    Curran MA, Allison JP. Tumor vaccines expressing Flt3 ligand synergize with CTLA-4 blockade to reject preimplanted tumors. Cancer Res 2009; 69:77477755.
  • 105
    Hirschhorn-Cymerman D, Rizzuto GA, Merghoub T et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med 2009; 206:11031116.
  • 106
    Ahmadzadeh M, Johnson L, Heemskerk B et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009; 114:15371544.