The Role of Regulatory T Cells in Cancer

다국어 초록 (Multilingual Abstract)

There has been an explosion of literature focusing on the role
of regulatory T (Treg) cells in cancer immunity. It is becoming
increasingly clear that Treg cells play an active and significant
role in the progression of cancer, and have an important role
in suppressing tumor-specific immunity. Thus, there is a clear
rationale for developing clinical strategies to diminish their
regulatory influences, with the ultimate goal of augmenting
antitimor immunity. Therefore, manipulation of Treg cells represent
new strategies for cancer treatment. In this Review, I
will summarize and review the explosive recent studies demonstrating
that Treg cells are increased in patients with malignancies
and restoration of antitumor immunity in mice and
humans by depletion or reduction of Treg cells. In addition, I
will discuss both the prognostic value of Treg cells in tumor
progression in tumor-bearing hosts and the rationale for
strategies for therapeutic vaccination and immunotherapeutic
targeting of Treg cells with drugs and microRNA.

다국어 초록 (Multilingual Abstract)

There has been an explosion of literature focusing on the role
of regulatory T (Treg) cells in cancer immunity. It is becoming
increasingly clear that Treg cells play an active and significant
role in the progression of cancer, and have an important role
in suppressing tumor-specific immunity. Thus, there is a clear
rationale for developing clinical strategies to diminish their
regulatory influences, with the ultimate goal of augmenting
antitimor immunity. Therefore, manipulation of Treg cells represent
new strategies for cancer treatment. In this Review, I
will summarize and review the explosive recent studies demonstrating
that Treg cells are increased in patients with malignancies
and restoration of antitumor immunity in mice and
humans by depletion or reduction of Treg cells. In addition, I
will discuss both the prognostic value of Treg cells in tumor
progression in tumor-bearing hosts and the rationale for
strategies for therapeutic vaccination and immunotherapeutic
targeting of Treg cells with drugs and microRNA.

참고문헌 (Reference)

1 Woo EY, "regulatory CD4(+) CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer" 61 : 4766-4772, 2001

2 Lindsay MA, "microRNAs and the immune response" 29 : 343-351, 2008

3 Mahnke K, "kinetics of Treg depletion and alterations in immune functions in vivo and in vitro" 120 : 2723-2733, 2007

4 Wan YY, "Yin-Yang functions of transforming growth factor-beta and T regulatory cells in immune regulation" 220 : 199-213, 2007

5 Hontsu S, "Visualization of naturally occurring Foxp3+ regulatory T cells in normal and tumor-bearing mice" 4 : 1785-1793, 2004

6 Nair S, "Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity" 67 : 371-380, 2007

7 Fu T, "Tumor-specific CD4(+) suppressor T-cell clone capable of inhibiting rejection of syngeneic sarcoma in A/J mice" 87 : 680-687, 2000

8 Lee CH, "Tumor-localized ligation of CD3 and CD28 with systemic regulatory T-cell depletion induces potent innate and adaptive antitumor response" 15 : 2756-2766, 2009

9 Siddiqui SA, "Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma" 13 : 2075-2081, 2007

10 Salama P, "Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer" 27 : 186-192, 2009

11 Lutsiak ME, "Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells" 180 : 5871-5881, 2008

12 Valzasina B, "Tumor-induced expansion of regulatory? T cells by conversion of CD4+CD25-lymphocytes is thymus and proliferation independent" 66 : 4488-4895, 2006

13 Onizuka S, "Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody" 59 : 3128-3133, 1999

14 Liu Z, "Tumor regulatory T cells potently abrogate antitimor immunity" 182 : 6160-6167, 2009

15 Jacob JB, "Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity" 182 : 5873-5881, 2009

16 Liu VC, "Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta" 178 : 2883-2892, 2007

17 Sharma S, "Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer" 65 : 5211-5220, 2005

18 Curiel TJ, "Tregs and rethinking cancer immunotherapy" 117 : 1167-1174, 2007

19 Curtin JF, "Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials" 3 : e1983-, 2008

20 Peng G, "Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function" 309 : 1380-1384, 2005

21 Waksman BH, "Tolerance, the thymus, and suppressor T cells" 28 : 363-374, 1977

22 Durkin HG, "Thymus and tolerance in Is regulation the major function of the thymus?" 182 : 33-57, 2001

23 Ha TY, "Thymic suppressor cell. I. Separation of subpopulation with suppressor activity" 139 : 13-23, 1974

24 Maggi E, "Thymic regulatory T cells" 4 : 579-586, 2005

25 Schreiber TH, "The use of FoxP3 as a biomarker and prognostic factor for malignant human tumors" 16 : 1931-1934, 2007

26 Block MS, "The tumor/immune interface:clinical evidence of cancer immunosurveillance, immunoediting and immunosubversion" 5 : 29-40, 2009

27 Ha TY, "The thymic suppressor cell. II. Metabolic requirement of suppressor activity" 3 : 351-359, 1974

28 Kosmaczewska A, "The significance of Treg cells in defective tumor immunity" 56 : 181-191, 2008

29 Ha TY, "The role of suppressor T cells in mycobacterial infection" 41 : 3-25, 2008

30 Ha TY, "The role of suppressor T cells in bacterial infections" 4 : 105-120, 2008

31 Yang ZZ, "The role of Treg cells in the cancer immunological response" 5 : 17-28, 2009

32 Matkowski R, "The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer" 29 : 2445-2451, 2009

33 Strauss L, "The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck" 13 : 6301-6311, 2007

34 Hubert P, "The cross-talk between dendritic and regulatory T cells: good or evil?" 82 : 781-794, 2007

35 Liu JY, "The changes of CD4+CD25+/CD4+proportion in spleen of tumor-bearing BALB/c mice" 3 : 5-, 2005

36 Lehe C, "The Wilms'tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy" 68 : 6350-6359, 2008

37 Danesse S, "The Janus face of CD4+CD25+ regulatory T cells in cancer and autoimmunity" 14 : 649-666, 2007

38 Francois V, "The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells" 69 : 4335-4345, 2009

39 Wolf D, "Telomere length of in vivo expanded CD4(+)CD25 (+) regulatory T-cells is preserved in cancer patients" 55 : 1198-1208, 2006

40 Schabowsky RH, "Targeting CD4+CD25+Foxp3+ regulatory T-cells for the augmentation of cancer immunotherapy" 8 : 1002-1008, 2007

41 Fietta AM, "Systemic inflammatory response and downmodulation of peripheral CD25+Foxp3+ T-regulatory cells in patients undergoing raidofrequency thermal ablation for lung cancer" 70 : 477-486, 2009

42 Sutmuller RP, "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" 194 : 823-832, 2001

43 Gershon RK, "Suppressor T cells" 108 : 586-590, 1972

44 Brahmachari S, "Suppression of regulatory T cells by? IL-12p40 homodimer via nitric oxide" 183 : 2045-2058, 2009

45 Orentas RJ, "Suppression of anti-cancer immunity by regulatory T cells: back to the future" 16 : 137-149, 2006

46 Curiel TJ, "Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival" 10 : 942-949, 2004

47 Ke X, "Roles of CD4+CD25(high)FOXP3 Tregs in lymphomas and tumors are complex" 13 : 3986-4001, 2008

48 Ha TY, "Role of the thymus in tolerance .X. Suppressor activity of antigen-stimulated rat thymocytes transferred to normal recipients" 110 : 1290-1299, 1973

49 Pallandre JR, "Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus- host disease and antitumor immunity" 179 : 7593-7604, 2007

50 Badoual C, "Revisiting the prognostic value of regulatory T cells in patients with cancer" 27 : e5-6, 2009

51 Nicholaou T, "Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients wih advanced malignant melanoma" 15 : 2166-2173, 2009

52 Chakraborty NG, "Regulatory T-cell response and tumor vaccine-induced cytotoxic T lymphocytes in human melanoma" 65 : 794-802, 2004

53 Yano H, "Regulatory T-cell function of adult T-cell leukemia/lymphoma cells" 120 : 2052-2057, 2007

54 Barnett BG, "Regulatory T cells: a new frontier in cancer immunotherapy. Adv Exp Med Biol 622;255-260, 2008 Daniel BJ, Coukos G, Zou W, Curiel TJ: Regulatory T cells:a new frontier in cancer immunotherapy" 622 : 255-260, 2008

55 Zou W, "Regulatory T cells, tumor immunity and immunotherapy" 6 : 295-307, 2006

56 Caramalho I, "Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide" 197 : 403-411, 2003

57 Gobert M, "Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome" 69 : 2000-2009, 2009

58 Beyer M, "Regulatory T cells in cancer" 108 : 804-811, 2006

59 Curiel TJ, "Regulatory T cells and treatment of cancer" 20 : 241-246, 2008

60 Mudd PA, "Regulatory T cells and systemic lupus erythematosus" 64 : 211-218, 2006

61 Wang RF, "Regulatory T cells and innate immune regulation in tumor immunity" 28 : 17-23, 2006

62 Wang HY, "Regulatory T cells and cancer" 19 : 217-223, 2007

63 Wang RF, "Regulatory T cells and Toll-like receptors in tumor immunity" 18 : 136-142, 2006

64 Beissert S, "Regulatory T cells" 126 : 15-24, 2006

65 Fontenot JD, "Regulatory T cell lineage specification by the forkhead transcription factor foxp3" 22 : 329-341, 2005

66 하대유, "Regulatory T Cell Therapy for Autoimmune Disease" 대한면역학회 8 (8): 107-123, 2008

67 Fujimoto S, "Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts" 116 : 800-806, 1976

68 Huang S, "Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications" 13 : 1362-1366, 2007

69 Beyer M, "Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine" 106 : 2018-2025, 2005

70 Mabarrack NH, "Recent thymic origin, differentiation, and turnover of regulatory T cells" 84 : 1287-1297, 2008

71 Wieczorek G, "Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue" 69 : 599-608, 2009

72 Bates GJ, "Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and hose at risk of late relapse" 24 : 5373-5380, 2006

73 Li, X, "Proportion of CD4CD25 regulatory T cell is increased in the patients with ovarian carcinoma" 23 : 399-403, 2005

74 El Andaloussi A, "Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors" 105 : 430-437, 2006

75 Badoual C, "Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers" 12 : 465-72, 2006

76 Leffers N, "Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesion of advanced stage ovarian cancer" 58 : 449-459, 2009

77 Liyanage UK, "Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma" 169 : 2756-2761, 2002

78 Hiraoka N, "Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions" 12 : 5423-5434, 2006

79 Hiraoka N, "Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions" 12 : 5423-5434, 2006

80 Ha TY, "Potentiation of anti-tumor immunity by modulation of suppressor T cells. II. Regression of tumor by modulation of suppressor T cells" 17 : 101-118, 1995

81 Juang CM, "Potential target in anticancer immunotherapy" 46 : 215-221, 2007

82 Ohara M, "Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer" 58 : 441-447, 2009

83 Zhou X, "Plasticity of CD4+Foxp3+ T cells" 21 : 281-285, 2009

84 Powell DJ Jr, "Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration" 31 : 189-198, 2008

85 Alvaro T, "Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells" 11 : 1467-1473, 2005

86 Fattorossi A, "Neoadjuvant therapy changes the lymphocyte composition of tumor-draining lymph nodes in cervical carcinoma" 100 : 1418-1428, 2004

87 Sakaguchi S, "Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune response" 22 : 531-562, 2004

88 Curotto de Lafaille MA, "Natural and adaptive Foxp3+ regulatory T cells: More of the same or a division of labor?" 30 : 626-635, 2009

89 Mailloux AW, "NK-dependent increases in CCL22 secretion selectively recruits regulatory T cells to the tumor microenvironment" 182 : 2753-2765, 2009

90 Lodish HF, "Micromanagement of the immune system by microRNAs" 8 : 120-130, 2008

91 Ventura A, "MicroRNAs and cancer: short RNAs go a long way" 136 : 586-591, 2009

92 Xiao C, "MicroRNA control in the immune system:basic principles" 136 : 26-36, 2009

93 Shevach EM, "Mechanisms of Toxp3+ T regulatory cell-medicated suppression" 30 : 636-645, 2009

94 Fattorossi A, "Lymphocyte compostion of tumor draining lymphnodes from cervical and endometrial cancer patients" 92 : 106-115, 2004

95 Quezada SA, "Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma" 205 : 2125-2138, 2008

96 Hueman MT, "Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine" 98 : 17-29, 2006

97 Powell DJ Jr, "Large-scale depletion of CD25+ regulatory T cells from patient leukapheresis samples" 28 : 403-411, 2005

98 Ling X, "Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice" 65 : 2532-2536, 2005

99 Gao Q, "Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection" 25 : 2586-2593, 2007

100 Yang ZZ, "Intratumoral CD4+CD25+regulatory T-cell-mediated suppression of infiltrating CD4+T-cells in B-cell non-Hodgkin lymphoma" 107 : 3639-3646, 2006

101 Yu P, "Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors" 201 : 779-791, 2005

102 Gershon RK, "Infectious immunological tolerance" 21 : 903-914, 1971

103 Shimizu J, "Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity" 5218 163 : 5211-, 1999

104 Walker MR, "Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells" 112 : 1437-1443, 2003

105 Tokuno K, "Increased prevalence of regulatory T-cells in the peripheral blood of patients with gastrointestinal cancer" 29 : 1527-1532, 2009

106 Ormandy LA, "Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma" 65 : 2457-2464, 2005

107 Ichihara F, "Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers" 9 : 4404-4408, 2003

108 Wang X, "Increased population of CD4+CD25high,regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients" 75 : 468-476, 2005

109 Jensen HK, "Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma" 15 : 1052-1058, 2009

110 Szczepanski MJ, "Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia" 15 : 3325-3332, 2009

111 Motta M, "Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia" 19 : 1788-1793, 2005

112 Mao C, "Increased CD4+CD25+FOXP3+regulatory T cells in cancer patients from conversion of CD4+CD25-T cells through tumor-derived factors" 31 : 243-248, 2008

113 Liyanage UK, "Increase prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma" 29 : 416-424, 2006

114 Wolf AM, "Increase of regulatory T cells in the peripheral blood of cancer patients" 9 : 606-612, 2003

115 Heimberger AB, "Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas" 14 : 5166-5172, 2008

116 Beyer M, "In vivo peripheral expansion of naive CD4+CD25highFoxp3+ regulatory T cells in patients with multiple myeloma" 107 : 3940-3949, 2006

117 Van Meirvenne S, "In vivo depletion of CD4+CD25+regulatory T cells enhances the antigen-specific primary and memory CTL response elicited by mature mRNA-electroporated dendritic cells" 12 : 922-932, 2005

118 Lizee G, "Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms" 12 : 4794-4803, 2006

119 Marshall NA, "Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma" 103 : 1755-1762, 2004

120 McCarter MD, "Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients" 14 : 2854-2860, 2007

121 Generali D, "Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer" 15 : 1046-1051, 2009

122 Sakaguchi S, "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanisms of self-tolerance causes various autoimmune diseases" 155 : 1151-1164, 1995

123 Dougan M, "Immune therapy for cancer" 27 : 83-117, 2009

124 Litzinger MT, "IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity" 110 : 3192-3201, 2007

125 Ahmadzadeh M, "IL-2 administration increases CD4+CD25(hi) Foxp3+regulatory T cells in cancer patients" 107 : 2409-2414, 2006

126 Riley JL, "Human T regulatory cell therapy: take a billion or so and call me in the morning" 30 : 656-665, 2009

127 Baecher-Allan C, "Human CD4+CD25+ regulatory T cells" 16 : 89-98, 2004

128 Leon K, "How regulatory CD25+CD4+ T cells impinge on tumor immunobiology:The differential response of tumors to therapies" 179 : 5659-5668, 2007

129 Carreras J, "High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma" 27 : 1470-1476, 2009

130 Carreras J, "High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma" 108 : 2957-2964, 2006

131 Wrzesinski C, "Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells" 117 : 492-501, 2007

132 Miyara M, "Functional delineation and differentiation dynamics of human CD4+ T cells expressing the Foxp3 transcription factor" 30 : 899-911, 2009

133 Miyara M, "Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor" 30 : 899-911, 2009

134 Lu LF, "Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein" 30 : 80-91, 2009

135 Viguier M, "Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells" 173 : 1444-1453, 2004

136 Shevach EM, "Fatal attraction: tumors beckon regulatory T cells" 10 : 900-901, 2004

137 Yang XF, "Factors regulating apoptosis and homeostasis of CD4+ CD25(high) FOXP3+ regulatory T cells are new therapeutic targets" 13 : 1472-1499, 2008

138 Ziegler SF, "FOXP3: of mice and men" 24 : 209-226, 2006

139 Kobayashi N, "FOXP3+ regulatory T cells affect the development and progression of hepatocarinogenesis" 13 : 902-911, 2007

140 Lu H, "FOXP3 expression and prognosis: role of both the tumor and T cells" 27 : 1735-1736, 2009

141 Merio A, "FOXP3 expression and overall survival in breast cancer" 27 : 1746-1752, 2009

142 Kryczek I, "FOXP3 defines regulatory T cells in human tumor and autoimmune disease" 69 : 3995-4000, 2009

143 Rozkova D, "FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer" 131 : 1-10, 2009

144 Karube K, "Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells" 126 : 81-84, 2004

145 van der Viliet HJ, "Exploiting regulatory T-cell populations for the imunotherapy of cancer" 30 : 591-595, 2007

146 Huen J, "Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?" 9 : 83-89, 2009

147 Dannull J, "Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells" 115 : 3623-3633, 2005

148 Wang W, "Effects of high-dose IFNα2b on regional lymph node metastases of human melanoma: Modulation of STAT5, FOXP3, and IL-17" 14 : 8314-8320, 2008

149 Lin YC, "Effector/memory but not naive regulatory T cells are responsible for the loss of concomitant tumor immunity" 182 : 6095-6104, 2009

150 Prabhala RH, "Dysfuntional T regulatory cells in multiple myeloma" 107 : 301-304, 2006

151 Qin FX, "Dynamic behavior and function of Foxp3+ regulatory T cells in tumor bearing host" 6 : 3-13, 2009

152 Kawaida H, "Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer" 124 : 151-157, 2005

153 Tan MC, "Distribution of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer" 182 : 1746-1755, 2009

154 Petrausch U, "Disruption of TGF-beta signaling prevents the generation of tumor-sensitized regulatory T cells and facilitates therapeutic antitumor immunity" 183 : 3682-3689, 2009

155 Toda A, "Development and function of naturally occurring CD4+CD25+ regulatory T cells" 80 : 458-470, 2006

156 Morse MA, "Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines" 112 : 610-618, 2008

157 Tanaka H, "Depletion of CD4+CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes" 25 : 207-217, 2002

158 Viel CT, "Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice" 13 : 1252-1258, 2006

159 Heier I, "Depletion of CD4+CD25+ regulatory T cells inhibits local tumour growth in a mouse model of B cell lymphoma" 152 : 381-387, 2008

160 Chen YL, "Depletion of CD4(+)CD25(+) regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma" 14 : 5797-5809, 2008

161 Golgher D, "Depletion of CD25+regulatory cells uncovers immune responses to shared murine tumor rejection antigens" 32 : 3267-3275, 2002

162 Wong BY, "Denileukin diftitox as novel targeted therapy for lymphoid malignancies" 25 : 495-501, 2007

163 Prasad SJ, "Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+regulatory T cells" 174 : 90-98, 2005

164 Jones E, "Deletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice" 2 : 1-, 2002

165 Foss FM, "DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma" 1 : 110-116, 2000

166 Kohlhaas S, "Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells" 182 : 2578-2582, 2009

167 Woo EY, "Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation" 168 : 4272-4276, 2002

168 Shafer-Weaver KA, "Cutting Edge: tumor-spe cific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells" 183 : 4848-4852, 2009

169 Ashley CW, "Cutting Edge: responder T cells regulate human DR+ effector regulatory T cell activity via granzyme B" 183 : 4843-4847, 2009

170 Turk MJ, "Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells" 200 : 771-782, 2004

171 Foss F, "Clinical experience with denileukin diftitox (ONTAK)" 33 : S11-16, 2006

172 Vence L, "Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma" 104 : 20884-20889, 2007

173 Schaefer C, "Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer" 92 : 913-920, 2005

174 Shevach EM, "Certified professionals: CD4+ CD25+ suppressor T cells" 193 : F41-46, 2001

175 Zitvogel L, "Cancer despite immunosurveillance:immunoselectionand immunosubversion" 6 : 715-727, 2006

176 Wing K, "CTLA-4 control over Foxp3+ regulatory T cell function" 322 : 271-275, 2008

177 Antony PA, "CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells" 174 : 2591-2601, 2005

178 Han Y, "CD69+ CD4+CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1" 182 : 111-120, 2009

179 Nishikawa H, "CD4＋CD25＋ regulatory Tcells control the induction of antigen-specific CD4＋ helper T cell responses in cancer patients" 106 : 1008-1011, 2005

180 Grauer OM, "CD4+Foxp3+regulatory T cells gradually accumulate in glioma during tumor growth and efficiently suppress antiglioma immue responses in vivo" 121 : 95-105, 2007

181 Miller AM, "CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients" 177 : 7398-7405, 2006

182 Javia LR, "CD4+CD25+suppressor lymphocytes in the circulation of patients immunized against melanoma antigens" 26 : 85-93, 2003

183 Shen LS, "CD4+CD25+CD127(low/?)regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression" 131 : 109-118, 2009

184 Sasada T, "CD4+CD25+ regulatory Tcells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression" 98 : 1089-1099, 2003

185 Ghiringhelli F, "CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative" 34 : 336-344, 2004

186 Xu H, "CD4+CD25+ regulatory T cells in patients with advanced gastrointestinal cancer treated with chemotherapy" 32 : 246-252, 2009

187 Elpek KG, "CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model" 178 : 6840-6648, 2007

188 Casares N, "CD4+/CD25+regulatory cells inhibit activation of tumorprimed CD4+Tcells with IFN-γ-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination" 171 : 5931-5939, 2003

189 Kono K, "CD4(+) CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers" 55 : 1064-1071, 2006

190 Linehan DC, "CD25+CD4+ regulatory T-cells in cancer" 32 : 155-168, 2005

191 Qin XJ, "CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion" 15 : 2231-2237, 2009

192 Mizukami Y, "CCL17 and CCL22 chemokines within tumor environment are related to accumulation of Toxp3+regulatory T cells in gastric cancer" 122 : 2286-2293, 2008

193 Olkhanud PB, "Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells" 69 : 5996-6004, 2009

194 Hiur T, "Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression" 175 : 5058-5066, 2005

195 Chin KM, "Biologic correlates of response and survival in patients with cutaneous T-cell lymphoma treated with denileukin diftitox" 7 : 199-204, 2006

196 Yang ZZ, "Attenuation of CD8(+) T-cell function by CD4(+)CD25(+)regulatory T cells in B-cell non-Hodgkin's lymphoma" 66 : 10145-10152, 2006

197 Jarnicki AG, "Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics" 180 : 3797-3806, 2008

198 Gray CP, "Association of increased levels of heavy-chain ferritin with increased CD4+CD25+regulatory T-cell levels in patients with melanoma" 9 : 2551-2559, 2003

199 Ruter J, "Altering regulatory T cell function in cancer immunotherapy: a novel means to boost the efficacy of cancer vaccines" 14 : 1761-1770, 2009

200 Tien AH, "Altered immunity accompanies disease progression in a mouse model of prostate dysplasia" 65 : 2947-2955, 2005

201 Powell DP Jr, "Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo" 179 : 4919-4928, 2007