T-regulatory cells in tumour-specific vaccination strategies

Expert Opinion on Biological Therapy

Volumn 8, Issue 9, 2008, Pages 1365-1379

  Welters, Marij J P ^a   Piersma, Sytse J ^a   van der Burg, Sjoerd H ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Cancer; Immunotherapy; Regulatory T cells; Vaccine

Indexed keywords

B7 ANTIGEN; BASILIXIMAB; BUSULFAN; CADHERIN; CD103 ANTIGEN; CD28 ANTIGEN; CD86 ANTIGEN; CHEMOKINE; CHEMOKINE RECEPTOR CCR7; CYCLOPHOSPHAMIDE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DENILEUKIN DIFTITOX; FLUDARABINE; GLUCOCORTICOID INDUCED TUMOR NECROSIS FACTOR RECEPTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR VACCINE; IMMUNOTOXIN LMB2; INTERLEUKIN 12; INTERLEUKIN 2 RECEPTOR; MACROPHAGE DERIVED CHEMOKINE; MELAN A; PERTUSSIS TOXIN; PHOSPHODIESTERASE III; SECONDARY LYMPHOID TISSUE CHEMOKINE; T LYMPHOCYTE RECEPTOR; THYMUS AND ACTIVATION REGULATED CHEMOKINE; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA;

ADAPTIVE IMMUNITY; ANTIGEN EXPRESSION; ANTIGEN PRESENTING CELL; APOPTOSIS; AUTOIMMUNITY; CANCER IMMUNIZATION; CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLINICAL TRIAL; DENDRITIC CELL; DOWN REGULATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; EFFECTOR CELL; HELPER CELL; HUMAN; IMMUNOTHERAPY; INNATE IMMUNITY; LOW DRUG DOSE; LYMPHOCYTE FUNCTION; LYMPHOCYTE MIGRATION; LYMPHOCYTE PROLIFERATION; LYMPHOCYTOPENIA; NATURAL KILLER CELL; NEOPLASM; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PROSTATE CANCER; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION; UPREGULATION;

ANIMALS; CANCER VACCINES; HUMANS; NEOPLASMS; T-LYMPHOCYTES, REGULATORY;

EID: 52949111320     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.8.9.1365     Document Type: Review

References (177)

1. Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol 2005;5:772-82
2. Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002;3:756-63
3. Fontenot JD, Dooley JL, Farr AG, Rudensky AY. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 2005;202:901-6
4. Aschenbrenner K, D'Cruz LM, Vollmann EH, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 2007;8:351-8
5. Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001;2:1032-9
6. Kyewski B, Klein L. A central role for central tolerance. Ann Rev Immunol 2006;24:571-606
7. Anderson MS, Venanzi ES, Chen Z, et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 2005;23:227-39
8. Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002;298:1395-401
9. Tarbell KV, Yamazaki S, Steinman RM. The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin Immunol 2006;18:93-102
10. Liu H, Leung BP. CD4+CD25+ regulatory T cells in health and disease. Clin Exp Pharmacol Physiol 2006;33:519-24
11. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann Rev Immunol 2004;22:531-62
12. Maloy KJ, Powrie F. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol 2005;6:1071-2
13. Scheffold A, Hühn J, Höfer T. Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL-)two to tango. Eur J Immunol 2005;35:1336-41
14. Li R, Perez N, Karumuthil-Melethil S, et al. Enhanced engagement of CTLA-4 Induces antigen-specific CD4+CD25+Foxp3+ and CD4+CD25 TGF-β1+ adaptive regulatory T Cells. J Immunol 2007;179:5191-203
15. Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 2007;13:108-16
16. Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C. GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol 2007;37:1165-9
17. Shevach EM, Stephens GL. The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat Rev Immunol 2006;6:613-8
18. Baltz KM, Krusch M, Bringmann A, et al. Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/ tumor cell interactions. FASEB J 2007;21:2442-54
19. So T, Lee SW, Croft M. Tumor necrosis factor/tumor necrosis factor receptor family members that positively regulate immunity. Int J Hematol 2006;83:1-11
20. Tuyaerts S, Van Meirvenne S, Bonehill A, et al. Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory T cells. J Leukoc Biol 2007;82:93-105
21. 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;202:885-91
22. Shimizu J, Yamazaki S, Takahashi T, et al. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135-42
23. Ronchetri S, Zollo O, Bruscoli S, et al. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 2004;34:613-22
24. Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 2005;35:1016-22
25. Caramalho I, Lopes-Carvalho T, Ostler D, et al. Regulatory T Cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J Exp Med 2003;197:403-11
26. Sutmuller RPM, Morgan ME, Netea MG, et al. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol 2006;27:387-93
27. Caron G, Duluc D, Fremaux I, et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-γ production by memory CD4+ T cells. J Immunol 2005;175:1551-7
28. Sutmuller RPM, den Brok MH, Kramer M, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006;116:485-94
29. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048-53
30. Crellin NK, Garcia RV, Hadistar O, et al. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 2005;175:8051-9
31. Peng G, Guo Z, Kiniwa Y, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005;309:1380-4
32. Kiniwa Y, Miyahara Y, Wang HY, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 2007;13:6947-58
33. Lehmann J, Huehn J, de la Rosa M, et al. Expression of the integrin αEβ7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells. Proc Natl Acad Sci USA 2002;99:13031-6
34. Yamaguchi T, Hirota K, Nagahama K, et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 2007;27:145-59
35. Hu S, Dai J, Wei H, et al. Functional and stable expression of recombinant human FOXP3 in bacterial cells and development of antigen-specific monoclonal antibodies. J Biochem 2007;142:471-80
36. Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006;126:375-87
37. Ono M. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007;446:685-9
38. Ziegler SF. FOXP3: of mice and men. Ann Rev Immunol 2006;24:209-26
39. Curiel TJ. Regulatory T-cell development: is Foxp3 the decider? Nat Med 2007;13:250-3
40. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science 2007;317:627-9
41. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-61
42. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6
43. 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;56:1743-53
44. Miller AM, Lundberg K, Ozenci V, et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 2006;177:7398-405
45. Woo EY, Chu CS, Goletz TJ, 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
46. Liyanage UK, Moore TT, Joo HG, 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
47. 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;103:6659-64
48. van der Burg SH, Piersma SJ, de Jong A, et al. Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens. Proc Natl Acad Sci USA 2007;104:12087-92
49. Allan SE, Passerini L, Bacchetta R, et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 2005; 115:3276-84
50. Yagi H, Nomura T, Nakamura K, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 2004;16:1643-56
51. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201:723-35
52. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-51
53. D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005;6:1152-9
54. Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007;445:771-5
55. Liu W, Putman AL, XuoYu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-11
56. Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693-700
57. Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206-12
58. Nakamura K, Kitani A, Fuss I, et al. TGF-β1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834-42
59. Bopp T, Becker C, Klein M, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007;204:1303-10
60. Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737-42
61. Strauss L, Bergmann C, Szczepanski M, et al. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res 2007;13:4345-54
62. Larmonier N, Marron M, Zeng Y, et al. Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10. Cancer Immunol Immunother 2007;56:48-59
63. Cools N, Ponsaerts P, Van Tendeloo VF, Berneman ZN. Regulatory T cells and human disease. Clin Dev Immunol 2007;2007:89195-206
64. Grossman WJ, Verbsky JW, Barchet W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21:589-601
65. Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004;104:2840-8
66. Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000;164:183-90
67. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006;25:195-201
68. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007;7:585-98
69. Carrier Y, Yuan J, Kuchroo VK, Weiner HL. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-β T cell-transgenic mice. J Immunol 2007;178:179-85
70. Zhang C, Zhang J, Tian Z. The regulatory effect of natural killer cells: do "NK-reg cells" exist? Cell Mol Immunol 2006;3:241-54
71. Jiang H, Chess L. Regulation of immune responses by T cells. N Engl J Med 2006;354:1166-76
72. Hauben E, Roncarolo MG. Human CD4+ regulatory T cells and activation-induced tolerance. Microbes Infect 2005;7:1023-32
73. Jonuleit H, Schmitt E, Schuler G, et al. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogentic immature human dendritic cells. J Exp Med 2000;192:1213-22
74. O'Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med 2004;10:801-5
75. Roncarolo MG, Gregori S, Battaglia M, et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006;212:28-50
76. Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002;195:603-16
77. Penna G, Giarratana N, Amuchastegui S, et al. Manipulating dendritic: cells to induce regulatory T cells. Microbes Infect 2005;7:1033-9
78. Bacchetta R, Sartirana C, Levings MK, et al. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 2002;32:2237-45
79. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med 2003;198:1875-86
80. Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256-60
81. Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007;204:1775-85
82. Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J Exp Med 2007;204:1757-64
83. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007;26:371-81
84. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007;8:345-50
85. Mahic M, Henjum K, Yaqub S, et al. Generation of highly suppressive adaptive CD8(+)CD25(+)FOXP3(+) regulatory T cells by continuous antigen stimulation. Eur J Immunol 2008;38:640-6
86. Steinbrink K, Graulich E, Kubsch S, et al. CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 2002;99:2468-76
87. Wei S, Kryczek I, Zou L, et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 2005;65:5020-6
88. Filaci G, Fenoglio D, Fravega M, et al. CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 2007;179:4323-34
89. Rohrer JW, Barsoum AL, Dyess DL, et al Human breast carcinoma patients develop clonable oncofetal antigen-specific effector and regulatory T lymphocytes. J Immunol 1999;162:6880-9
90. Akagi J, Takai E, Tamori Y, Ogawa M. CD3+CD56+CD8+ cells demonstrating a suppressor T cell-like function in the peripheral blood of colon cancer patients. Int J Oncol 2001;19:561-6
91. Rohrer JW, Coggin JH Jr. CD8 T cell clones inhibit antitumor T cell function by secreting IL-10. J Immunol 1995;155:5719-27
92. Wolf AM, Wolf D, Steurer M, et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003;9:606-12
93. Ling KL, Pratap SE, Bates GJ, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 2007;7:7
94. den Boer AT, van Mierlo GJ, Fransen MF, et al. CD4+ T cells are able to promote tumor growth through inhibition of tumor-specific CD8+ T-cell responses in tumor-bearing hosts. Cancer Res 2005;65:6984-9
95. Hiura T, Kagamu H, Miura S, et al. Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression. J Immunol 2007;175:5058-66
96. Wang HY, Lee DA, Peng G, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 2004;20:107-18
97. Viguier M, Lemaître F, Verola O, et al. 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
98. Piersma SJ, Jordanova ES, van Poelgeest MIE, et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 2007;67:354-61
99. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-9
100. Wolf D, Wolf AM, Rumpold H, et al. 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
101. Unitt E, Marshall A, Gelson W, et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 2006;45:246-53
102. Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-39
103. 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;102:18538-43
104. Gjerdrum LM, Woetmann A, Odum N, et al. FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. Leukemia 2007;21:2512-8
105. 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;24:5373-80
106. 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;12:5423-34
107. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 2006;107:2866-72
108. 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;25:2586-93
109. Kobayashi N, Hiraoka N, Yamagami W, et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 2007;13:902-11
110. Alvaro T, Lejeune M, Salvado MT, 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
111. 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;14:2028-35
112. Dercamp C, Chemin K, Caux C, et al. Distinct and overlapping roles of interleukin-10 and CD25+ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res 2005;65:8479-86
113. Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779-91
114. Chaput N, Darrasse-Jeze G, Bergot A-S, et al. Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 th cells at tumor sites. J Immunol 2007;179:4969-78
115. Jarnicki AG, Lysaght J, Todryk S, Mills KH. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 2006;177:896-904
116. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-9
117. Casares N, Arribillaga L, Sarobe P, et al. CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-γ-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 2003;171:5931-9
118. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-53
119. Sojka DK, Hughson A, Sukiennicki TL, Fowell DJ. Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity. J Immunol 2005;175:7274-80
120. Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of human CD4(+)CD25(+high) regulatory T cell function. J Immunol 2002;169:6210-7
121. Yang ZZ, Novak AJ, Stenson MJ, et al. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 2006;107:3639-46
122. 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;122:2286-93
123. 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;66:5716-22
124. Flanagan K, Moroziewicz D, Kwak H, et al. The lymphoid chemokine CCL21 costimulates naive T cell expansion and Th1 polarization of non-regulatory CD4+ T cells. Cell Immunol 2004;231:75-84
125. Wang HY, Peng G, Guo Z, et al. 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
126. 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
127. 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
128. Zhou G, Drake CG, Levitsky HI. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 2006;107:628-36
129. Molling JW, de Gruijl TD, Glim J, et al. CD4(+)CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia. Int J Cancer 2007;121:1749-55
130. Piersma SJ, Welters MJP, van der Burg SH. Tumour-specific regulatory T cells in cancer patients. Hum Immunol 2008; In press
131. Welters MJP, van der Logt P, van den Eeden SJF, et al. Detection of human papillomavirus type 18 E6 and E7-specific CD4+ T-helper 1 immunity in relation to health versus disease. Int J Cancer 2006;118:950-6
132. De Jong A, van Poelgeest MIE, van der Hulst JM, et al. Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6. Cancer Res 2004;64:5449-55
133. van der Burg SH, Ressing ME, Kwappenberg KM, et al. Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes. Int J Cancer 2001;91:612-8
134. van der Burg SH, de Jong A, Welters MJP, et al. The status of HPV16-specific T-cell reactivity in health and disease as a guide to HPV vaccine development. Virus Res 2002;89:275-84
135. Welters MJP, de Jong A, van den Eeden SJF, et al. Frequent display of human papillomavirus type 16 E6-specific memory T-helper cells in the healthy poulation as witness of previous viral encounter. Cancer Res 2003;63:636-41
136. Mocellin S, Mandruzzato S, Bronte V, Marincola FM. Cancer vaccines: pessimism in check. Nat Med 2004;10:1278-9
137. Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol 2004;4:46-54
138. Nair RE, Kilinc MO, Jones SA, Egilmez NK. Chronic immune therapy induces a progressive increase in intratumoral T suppressor activity and a concurrent loss of tumor-specific CD8+ T effectors in her-2/neu transgenic mice bearing advanced spontaneous tumors. J Immunol 2006;176:7325-34
139. Nishikawa H, Kato T, Tawara I, et al. Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells. J Exp Med 2005;201:681-6
140. Welters MJP, Kenter GG, Piersma SJ, et al. Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by an HPV16 E6 and E7 long-peptide vaccine. Clin Cancer Res 2008;14:178-87
141. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic 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;155:1151-64
142. Pakravan N, Hassan ATM, Hassan ZM. Naturally occurring self-reactive CD4+CD25+ regulatory T cells: universal immune code. Cell Mol Immunol 2007;4:197-201
143. Rouse BT. Regulatory T cells in health and disease. J Intern Med 2007;262:78-95
144. Wilczynski JR, Kalinka J, Radwan M. The role of T-regulatory cells in pregnancy and cancer. Front Biosci 2008;13:2275-89
145. Wilczynski JR, Radwan M, Kalinka J. The characterization and role of regulatory T cells in immune reactions. Front Biosci 2008;13:2266-74
146. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007;8:191-7
147. Le Bras S, Geha RS. IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Invest 2006;116:1473-5
148. Zou W. Regulatory T cells, tumour immunity and immunotherapy, Nat Rev Immunol 2006;6:295-307
149. Onizuka S, Tawara I, Shimizu J, et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res 1999;59:3128-33
150. 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;194:823-32
151. Prasad SJ, Farrand KJ, Matthews SA, et al. 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;174:90-8
152. 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;115:3623-33
153. Vieweg J, Su Z, Dahm P, Kusmartsev S. Reversal of tumor-mediated immunosuppression. Clin Cancer Res 2007;13:727s-732s
154. Kudo-Saito C, Schlom J, Camphausen K, et al. The requirement of multimodal therapy (vaccine, local tumor radiation, and reduction of suppressor cells) to eliminate established tumors. Clin Cancer Res 2005;11:4533-44
155. Li L, Okino T, Sugie T, et al. Cyclophosphamide given after active specific immunization augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells. J Surg Oncol 1998;67:221-7
156. Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1991;20:194-208
157. 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;34:336-44
158. Vierboom MP, Bos GM, Ooms M, et al. Cyclophosphamide enhances anti-tumor effect of wild-type p53-specific CTL. Int J Cancer 2000;87:253-60
159. Lutsiak ME, Semnani RT, Pascalis R, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862-8
160. Berd D, Mastrangelo MJ. Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset. Cancer Res 1987;47:3317-21
161. 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;56:641-8
162. 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;177:2136-40
163. 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;150:523-30
164. Barnett B, Kryczek I, Cheng P, et al. Regulatory T cells in ovarian cancer: biology and therapeutic potential. Am J Reprod Immunol 2005;54:369-77
165. Attia P, Maker AV, Haworth LR, et al. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 2005;28:582-92
166. Mahnke K, Schonfeld K, Fondel S, et al. Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int J Cancer 2007;120:2723-33
167. Dang NH, Fayad L, McLaughlin P, et al. Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma. Br J Haematol 2007;138:502-5
168. Cassan C, Piaggio E, Zappulla JP, et al. Pertussis toxin reduces the number of splenic Foxp3+ regulatory T cells. J Immunol 2006;177:1552-60
169. Chen X, Winkler-Pickett RT, Carbonetti NH, et al. Pertussis toxin as an adjuvant suppresses the number and function of CD4+CD25+ T regulatory cells. Eur J Immunol 2006;36:671-80
170. Powell DJ, Jr., Felipe-Silva A, Merino MJ, er 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;179:4919-28
171. Bijker MS, Melief CJ, Offringa R, van der Burg SH. Design and development of synthetic peptide vaccines: past, present and future. Expert Rev Vaccines 2007;6:591-603
172. Bijker MS, van den Eeden SJ, Franken KL, et al. CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J Immunol 2007;179:5033-40
173. van der Burg SH, Bijker MS, Welters MJ, et al. Improved peptide vaccine strategies, creating synthetic artificial infections to maximize immune efficacy. Adv Drug Deliv Rev 2006;58:916-30
174. Appay V, Voelter V, Rufer N, et al. Combination of transient lymphodepletion with busulfan and fludarabine and peptide vaccination in a phase I clinical trial for patients with advanced melanoma. J Immunother 2007;30:240-50
175. Taleb S, Herbin O, Ait-Oufella H, et al. Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. Arterioscler Thromb Vasc Biol 2007;27:2691-8
176. De Rosa V, Procaccini C, Cali G, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007;26:241-55
177. van der Burg SH. Therapeutic vaccines in cancer: moving from immunomonitoring to immunoguiding. Expert Rev Vaccines 2008;7:1-5