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