How numbers, nature, and immune status of Foxp3+ regulatory T-cells shape the early immunological events in tumor development

Frontiers in Immunology

Volumn 4, Issue SEP, 2013, Pages

  Darrasse Jèze, Guillaume ^a,b,c   Podsypanina, Katrina ^d  

^a UNIVERSITÉ PARIS DESCARTES   (France)

^b HÔPITAL NECKER ENFANTS MALADES   (France)

^c INSTITUT NECKER ENFANTS MALADES   (France)

^d MCGILL UNIVERSITY   (Canada)

Author keywords

Cancer; Early immune response; Foxp3; Memory; Tolerance; Treg; Tumor cells; Vaccination

Indexed keywords

TRANSCRIPTION FACTOR FOXP3;

APOPTOSIS; CANCER GROWTH; CANCER INFILTRATION; CANCER SURVIVAL; CD4+ CD25+ T LYMPHOCYTE; CELL PROLIFERATION; DISEASE ERADICATION; DOWN REGULATION; HUMAN; IMMUNE RESPONSE; IMMUNOSURVEILLANCE; NONHUMAN; PROGNOSIS; REGULATORY T LYMPHOCYTE; REVIEW;

EID: 84885969012     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00292     Document Type: Review

References (136)

1. Melero I, Bach N, Chen L. Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumor antigens. Life Sci (1997) 60:2035-41. doi: 10.1016/S0024-3205(96)00686-8.
2. Ochsenbein AF, Klenerman P, Karrer U, Ludewig B, Pericin M, Hengartner H, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA (1999) 96:2233-8. doi:10.1073/pnas.96.5.2233.
3. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature (2001) 411:1058-64. doi:10.1038/35082583.
4. Hewitt HB, Blake ER, Walder AS. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br J Cancer (1976) 33:241-59. doi:10.1038/bjc.1976.37.
5. Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mule JJ, Rosenberg SA, et al. Identification of human cancers deficient in antigen processing. J Exp Med (1993) 177:265-72. doi:10.1084/jem.177.2.265.
6. Spataro V, Norbury C, Harris AL. The ubiquitin-proteasome pathway in cancer. Br J Cancer (1998) 77:448-55. doi:10.1038/bjc.1998.71.
7. Cromme FV, Airey J, Heemels MT, Ploegh HL, Keating PJ, Stern PL, et al. Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas. J Exp Med (1994) 179:335-40. doi:10.1084/jem.179.1.335.
8. Whiteside TL, Stanson J, Shurin MR, Ferrone S. Antigen-processing machinery in human dendritic cells: up-regulation by maturation and down-regulation by tumor cells. J Immunol (2004) 173:1526-34.
9. Marzo AL, Lake RA, Lo D, Sherman L, Mcwilliam A, Nelson D, et al. Tumor antigens are constitutively presented in the draining lymph nodes. J Immunol (1999) 162:5838-45.
10. Robinson BW, Scott BM, Lake RA, Stumbles PA, Nelson DJ, Fisher S, et al. Lack of ignorance to tumor antigens: evaluation using nominal antigen transfection and T-cell receptor transgenic lymphocytes in Lyons-Parish analysis-implications for tumor tolerance. Clin Cancer Res (2001) 7:811s-7s.
11. Cuenca A, Cheng F, Wang H, Brayer J, Horna P, Gu L, et al. Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res (2003) 63:9007-15.
12. Rosenberg SA, Sherry RM, Morton KE, Scharfman WJ, Yang JC, Topalian SL, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Immunol (2005) 175:6169-76.
13. Ehrlich P. Ueber den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd (1909) 5:273-90.
14. Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res (1953) 13:835-7.
15. Burnet FM. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J (1957) 1(5023):841-7. doi:10.1136/bmj.1.5023.841.
16. Klein G. Tumor antigens. Annu Rev Microbiol (1966) 20:223-52. doi:10.1146/annurev.mi.20.100166.001255.
17. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature (2001) 410:1107-11. doi:10.1038/35074122.
18. Stutman O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science (1974) 183:534-6. doi:10.1126/science.183.4124.534.
19. Stutman O. Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous matings and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst (1979) 62:353-8.
20. Gallo-Hendrikx E, Percy D, Copps J, Mckeown B, Quinton M, McMillan I, et al. Evaluation of three lines of immunodeficient mice for the study of spontaneous metastatic tumors. APMIS (1999) 107:245-56. doi:10.1111/j.1699-0463.1999.tb01551.x.
21. Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature (2005) 437:141-6. doi:10.1038/nature03954.
22. Gorelik E, Wiltrout RH, Okumura K, Habu S, Herberman RB. Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J Cancer (1982) 30:107-12. doi:10.1002/ijc.2910300118.
23. Haliotis T, Ball JK, Dexter D, Roder JC. Spontaneous and induced primary oncogenesis in natural killer (NK)-cell-deficient beige mutant mice. Int J Cancer (1985) 35:505-13. doi:10.1002/ijc.2910350414.
24. Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA (2000) 97:2731-6. doi:10.1073/pnas.050588297.
25. Fodstad O, Hansen CT, Cannon GB, Boyd MR. Immune characteristics of the beige-nude mouse. A model for studying immune surveillance. Scand J Immunol (1984) 20:267-72. doi:10.1111/j.1365-3083.1984.tb01002.x.
26. Fodstad O, Hansen CT, Cannon GB, Statham CN, Lichtenstein GR, Boyd MR. Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects. Cancer Res (1984) 44:4403-8.
27. Hollenbeak CS, Todd MM, Billingsley EM, Harper G, Dyer AM, Lengerich EJ. Increased incidence of melanoma in renal transplantation recipients. Cancer (2005) 104:1962-7. doi:10.1002/cncr.21404.
28. Beral V, Newton R. Overview of the epidemiology of immunodeficiency-associated cancers. J Natl Cancer Inst Monogr (1998) 23:1-6. doi:10.1093/oxfordjournals.jncimonographs.a024164.
29. Mueller N. Overview of the epidemiology of malignancy in immune deficiency. J Acquir Immune Defic Syndr (1999) 21(Suppl 1):S5-10.
30. Dal Maso L, Serraino D, Franceschi S. Epidemiology of AIDS-related tumours in developed and developing countries. Eur J Cancer (2001) 37:1188-201. doi:10.1016/S0959-8049(01)00120-4.
31. Oluwole SF, Ali AO, Shafaee Z, Depaz HA. Breast cancer in women with HIV/AIDS: report of five cases with a review of the literature. J Surg Oncol (2005) 89:23-7. doi:10.1002/jso.20171.
32. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, 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) 102:18538-43. doi:10.1073/pnas.0509182102.
33. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med (2003) 348:203-13. doi:10.1056/NEJMoa020177.
34. Sakakura T, Nishizuka Y. Effect of thymectomy on mammary tumorigenesis, noduligenesis, and mammogenesis in the mouse. Gann (1967) 58:441-50.
35. Kojima A, Taguchi O, Sakakura T, Nishizuka Y. Prevalent types of tumors developing in neonatally thymectomized mice. Gann (1979) 70:839-43.
36. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science (1969) 166:753-5. doi:10.1126/science.166.3906.753.
37. Fujimoto S, Greene M, Sehon AH. Immunosuppressor T cells in tumor bearing host. Immunol Commun (1975) 4:201-17.
38. Fujimoto S, Greene MI, Sehon AH. Regualtion of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts. J Immunol (1976) 116:791-9.
39. Fujimoto S, Greene MI, Sehon AH. Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts. J Immunol (1976) 116:800-6.
40. Berendt MJ, North RJ. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J Exp Med (1980) 151:69-80. doi:10.1084/jem.151.1.69.
41. 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) 163:5211-8.
42. 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) 59:3128-33.
43. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res (2001) 61:4766-72.
44. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, 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.
45. Somasundaram R, Jacob L, Swoboda R, Caputo L, Song H, Basak S, et al. Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res (2002) 62:5267-72.
46. Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol (2002) 168:4272-6.
47. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res (2003) 9:606-12.
48. deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res (2012) 18:3022-9. doi:10.1158/1078-0432.CCR-11-3216.
49. 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. doi:10.1002/cncr.11618.
50. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, 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) 34:336-44. doi:10.1002/eji.200324181.
51. Liu JY, Zhang XS, Ding Y, Peng RQ, Cheng X, Zhang NH, et al. The changes of CD4+CD25+/CD4+ proportion in spleen of tumor-bearing BALB/c mice. J Transl Med (2005) 3:5. doi:10.1186/1479-5876-3-5.
52. Darrasse-Jeze G, Bergot AS, Durgeau A, Billiard F, Salomon BL, Cohen JL, et al. Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice. J Clin Invest (2009) 119:2648-62. doi:10.1172/JCI36628.
53. Martin F, Ladoire S, Mignot G, Apetoh L, Ghiringhelli F. Human FOXP3 and cancer. Oncogene (2010) 29:4121-9. doi:10.1038/onc.2010.174.
54. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron (2012) 6(2):147-57. doi:10.1007/s12307-012-0122-y.
55. Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J, et al. Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res (2005) 11:1467-73. doi:10.1158/1078-0432.CCR-04-1869.
56. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood (2006) 108:2957-64. doi:10.1182/blood-2006-04-018218.
57. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother (2009) 60:909-18. doi:10.1007/s00262-011-1046-y.
58. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol (2009) 27:186-92. doi:10.1200/JCO.2008.18.7229.
59. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother (2010) 33:435-41. doi:10.1097/CJI.0b013e3181d32f01.
60. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med (2004) 10:942-9. doi:10.1038/nm1093.
61. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood (2006) 107:3639-46. doi:10.1182/blood-2005-08-3376.
62. Gutierrez-Ramos JC, Lloyd C, Kapsenberg ML, Gonzalo JA, Coyle AJ. Non-redundant functional groups of chemokines operate in a coordinate manner during the inflammatory response in the lung. Immunol Rev (2000) 177:31-42. doi:10.1034/j.1600-065X.2000.17713.x.
63. Ghoreschi K, Laurence A, Yang XP, Tato CM, Mcgeachy MJ, Konkel JE, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature (2010) 467:967-71. doi:10.1038/nature09447.
64. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos 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) 198:1875-86. doi:10.1084/jem.20030152.
65. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25-precursors. J Immunol (2002) 169:4183-9.
66. 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) 66:4488-95. doi:10.1158/0008-5472.CAN-05-4217.
67. Zhou G, Levitsky HI. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol (2007) 178:2155-62.
68. Heldin CH, Miyazono K, Ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature (1997) 390:465-71. doi:10.1038/37284.
69. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev (2000) 14:627-44. doi:10.1101/gad.14.6.627.
70. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med (2001) 7:1118-22. doi:10.1038/nm1001-1118.
71. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, 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) 178:2883-92.
72. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res (2007) 67:8344-50. doi:10.1158/0008-5472.CAN-06-3304.
73. Moo-Young TA, Larson JW, Belt BA, Tan MC, Hawkins WG, Eberlein TJ, et al. Tumor-derived TGF-beta mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer. J Immunother (2009) 32:12-21. doi:10.1097/CJI.0b013e318189f13c.
74. Liyanage UK, Goedegebuure PS, Moore TT, Viehl CT, Moo-Young TA, Larson JW, et al. Increased prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother (2006) 29:416-24. doi:10.1097/01.cji.0000205644.43735.4e.
75. Baratelli F, Lee JM, Hazra S, Lin Y, Walser TC, Schaue D, et al. PGE(2) contributes to TGF-beta induced T regulatory cell function in human non-small cell lung cancer. Am J Trans Res (2010) 2:356-67.
76. Terabe M, Ambrosino E, Takaku S, O'Konek JJ, Venzon D, Lonning S, et al. Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res (2009) 15:6560-9. doi:10.1158/1078-0432.CCR-09-1066.
77. Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity (2006) 25:455-71. doi:10.1016/j.immuni.2006.07.011.
78. Li Z, Pang Y, Gara SK, Achyut BR, Heger C, Goldsmith PK, et al. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-beta in breast cancer progression. Int J Cancer (2012) 131:2584-95. doi:10.1002/ijc.27572.
79. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, 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) 202:919-29. doi:10.1084/jem.20050463.
80. Lebson L, Wang T, Jiang Q, Whartenby KA. Induction of the glucocorticoid-induced leucine zipper gene limits the efficacy of dendritic cell vaccines. Cancer Gene Ther (2011) 18:563-70. doi:10.1038/cgt.2011.23.
81. Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, et al. Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature (2007) 449:361-5. doi:10.1038/nature06110.
82. Birnberg T, Bar-On L, Sapoznikov A, Caton ML, Cervantes-Barragan L, Makia D, et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity (2008) 29:986-97. doi:10.1016/j.immuni.2008.10.012.
83. Darrasse-Jeze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao KH, et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med (2009) 206:1853-62. doi:10.1084/jem.20090746.
84. Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med (2009) 206:549-59. doi:10.1084/jem.20082394.
85. Billiard F, Lobry C, Darrasse-Jeze G, Waite J, Liu X, Mouquet H, et al. Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice. J Exp Med (2012) 209:1011-28. doi:10.1084/jem.20111615.
86. 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. doi:10.1016/j.immuni.2005.01.016.
87. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+ CD25-CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci USA (2005) 102:4091-6. doi:10.1073/pnas.0408679102.
88. Schallenberg S, Tsai PY, Riewaldt J, Kretschmer K. Identification of an immediate Foxp3(-) precursor to Foxp3(+) regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J Exp Med (2010) 207:1393-407. doi:10.1084/jem.20100045.
89. Wang C, Lee JH, Kim CH. Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch. PLoS ONE (2012) 7:e30793. doi:10.1371/journal.pone.0030793.
90. Zabransky DJ, Nirschl CJ, Durham NM, Park BV, Ceccato CM, Bruno TC, et al. Phenotypic and functional properties of Helios+ regulatory T cells. PLoS ONE (2012) 7:e34547. doi:10.1371/journal.pone.0034547.
91. Getnet D, Grosso JF, Goldberg MV, Harris TJ, Yen HR, Bruno TC, et al. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol Immunol (2010) 47:1595-600. doi:10.1016/j.molimm.2010.02.001.
92. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol (2010) 184:3433-41. doi:10.4049/jimmunol.0904028.
93. Verhagen J, Wraith DC. Comment on "Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells". J Immunol (2010) 185:7129. doi:10.4049/jimmunol.1090105 author reply 7130,.
94. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science (2013) 339:1219-24. doi:10.1126/science.1233913.
95. Paiva RS, Lino AC, Bergman ML, Caramalho I, Sousa AE, Zelenay S, et al. Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery. Proc Natl Acad Sci USA (2013) 110:6494-9. doi:10.1073/pnas.1221955110.
96. Bhatnagar RM, Zabriskie JB, Rausen AR. Cellular immune responses to methylcholanthrene-induced fibrosarcoma in BALB/c mice. J Exp Med (1975) 142:839-55. doi:10.1084/jem.142.4.839.
97. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci USA (2003) 100:10902-6. doi:10.1073/pnas.1834479100.
98. Vence L, Palucka AK, Fay JW, Ito T, Liu YJ, Banchereau J, et al. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci USA (2007) 104:20884-9. doi:10.1073/pnas.0710557105.
99. Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity (2004) 20:107-18. doi:10.1016/S1074-7613(03)00359-5.
100. Wang HY, Peng G, Guo Z, Shevach EM, Wang RF. Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol (2005) 174:2661-70.
101. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res (2006) 66:9290-8. doi:10.1158/0008-5472.CAN-06-1819.
102. Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE (2010) 5:e11469. doi:10.1371/journal.pone.0011469.
103. Fisson S, Darrasse-Jèze G, Litvinova E, Septier F, Klatzmann D, Liblau R, et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med (2003) 198:737-46. doi:10.1084/jem.20030686.
104. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood (2006) 108:3371-8. doi:10.1182/blood-2006-02-005660.
105. Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, et al. Developmental stage, phenotype, and migration distinguish naive-and effector/memory-like CD4+ regulatory T cells. J Exp Med (2004) 199:303-13. doi:10.1084/jem.20031562.
106. Setiady YY, Ohno K, Samy ET, Bagavant H, Qiao H, Sharp C, et al. Physiologic self antigens rapidly capacitate autoimmune disease-specific polyclonal CD4+ CD25+ regulatory T cells. Blood (2006) 107:1056-62. doi:10.1182/blood-2005-08-3088.
107. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med (1982) 155:1063-74. doi:10.1084/jem.155.4.1063.
108. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood (2005) 105:2862-8. doi:10.1182/blood-2004-06-2410.
109. Weiss VL, Lee TH, Song H, Kouo TS, Black CM, Sgouros G, et al. Trafficking of high avidity HER-2/neu-specific T cells into HER-2/neu-expressing tumors after depletion of effector/memory-like regulatory T cells. PLoS ONE (2012) 7:e31962. doi:10.1371/journal.pone.0031962.
110. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The central role of CD4(+) T cells in the antitumor immune response. J Exp Med (1998) 188:2357-68. doi:10.1084/jem.188.12.2357.
111. Overwijk WW, Lee DS, Surman DR, Irvine KR, Touloukian CE, Chan CC, et al. Vaccination with a recombinant vaccinia virus encoding a "self" antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes. Proc Natl Acad Sci USA (1999) 96:2982-7. doi:10.1073/pnas.96.6.2982.
112. Lollini PL, Cavallo F, Nanni P, Forni G. Vaccines for tumour prevention. Nat Rev Cancer (2006) 6:204-16. doi:10.1038/nrc1815.
113. Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci USA (2007) 104:19954-9. doi:10.1073/pnas.0704397104.
114. Wehrens EJ, Mijnheer G, Duurland CL, Klein M, Meerding J, Van Loosdregt J, et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood (2011) 118:3538-48. doi:10.1182/blood-2010-12-328187.
115. Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S. CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood (2005) 106:1008-11. doi:10.1182/blood-2005-02-0607.
116. Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol (2000) 30:1538-43. doi:10.1002/1521-4141(200006)30:6<1538::AID-IMMU1538>3.0.CO;2-X.
117. Dubey C, Croft M, Swain SL. Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. J Immunol (1996) 157:3280-9.
118. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med (2005) 353:2654-66. doi:10.1056/NEJMoa051424.
119. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (2006) 313:1960-4. doi:10.1126/science.1129139.
120. Holtan SG, Creedon DJ, Haluska P, Markovic SN. Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. Mayo Clin Proc (2009) 84:985-1000. doi:10.1016/S0025-6196(11)60669-1.
121. Chen T, Darrasse-Jeze G, Bergot AS, Courau T, Churlaud G, Valdivia K, et al. Self-specific memory regulatory T cells protect embryos at implantation in mice. J Immunol (2013) 191:2273-81. doi:10.4049/jimmunol.1202413.
122. Wen Y, Fang W, Xiang LX, Pan RL, Shao JZ. Identification of Treg-like cells in Tetraodon: insight into the origin of regulatory T subsets during early vertebrate evolution. Cell Mol Life Sci (2011) 68:2615-26. doi:10.1007/s00018-010-0574-5.
123. Quintana FJ, Iglesias AH, Farez MF, Caccamo M, Burns EJ, Kassam N, et al. Adaptive autoimmunity and Foxp3-based immunoregulation in zebrafish. PLoS ONE (2010) 5:e9478. doi:10.1371/journal.pone.0009478.
124. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell (2012) 150:29-38. doi:10.1016/j.cell.2012.05.031.
125. DePinho RA. The age of cancer. Nature (2000) 408:248-54. doi:10.1038/35041694.
126. Zhou G, Drake CG, Levitsky HI. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood (2006) 107:628-36. doi:10.1182/blood-2005-07-2737.
127. Ebert LM, Macraild SE, Zanker D, Davis ID, Cebon J, Chen W. A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma. PLoS ONE (2012) 7:e48424. doi:10.1371/journal.pone.0048424.
128. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest (2005) 115:3623-33. doi:10.1172/JCI25947.
129. Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr., et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Trans Med (2012) 4:134ra162. doi:10.1126/scitranslmed.3003330.
130. Tan C, Reddy V, Dannull J, Ding E, Nair SK, Tyler DS, et al. Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model. J Transl Med (2013) 11:148. doi:10.1186/1479-5876-11-148.
131. Taieb J, Chaput N, Schartz N, Roux S, Novault S, Menard C, et al. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol (2006) 176:2722-9.
132. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res (2013) 73:3591-603. doi:10.1158/0008-5472.CAN-12-4100.
133. Hirayama M, Nishikawa H, Nagata Y, Tsuji T, Kato T, Kageyama S, et al. Overcoming regulatory T-cell suppression by a lyophilized preparation of Streptococcus pyogenes. Eur J Immunol (2013) 43:989-1000. doi:10.1002/eji.201242800.
134. Chaput N, Darrasse-Jeze G, Bergot AS, Cordier C, Ngo-Abdalla S, Klatzmann D, et al. Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites. J Immunol (2007) 179:4969-78.
135. Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai M, et al. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Sci Trans Med (2010) 2:41ra52. doi:10.1126/scitranslmed.3001302.
136. Bergot AS, Durgeau A, Levacher B, Colombo BM, Cohen JL, Klatzmann D. Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells. Cancer Gene Ther (2010) 17:645-54. doi:10.1038/cgt.2010.21.