Tumor infiltrating regulatory T cells: Tractable targets for immunotherapy

International Reviews of Immunology

Volumn 29, Issue 5, 2010, Pages 461-484

  Khan, Adnan R ^a   Dovedi, Simon J ^b   Wilkinson, Robert W ^c   Pritchard, David I ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

^c ASTRAZENECA   (United Kingdom)

Author keywords

CCL22; CCR4; CTLA 4; GITR; regulatory T cell; tumor

Indexed keywords

ABN 912; ANTIDIABETIC AGENT; ANTIGOUT AGENT; BMS 741672; CCX 140; DACARBAZINE; DENILEUKIN DIFTITOX; GLYCOPROTEIN GP 100; IMATINIB; INCB 8696; IPILIMUMAB; MK 0812; PLERIXAFOR; SUNITINIB; UNCLASSIFIED DRUG;

AUTOIMMUNE DISEASE; CELL CONTACT; CELL FUNCTION; CELL MIGRATION; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; DRUG MECHANISM; GASTROINTESTINAL STROMAL TUMOR; HUMAN; IMMUNE RESPONSE; IMMUNOPATHOLOGY; IMMUNOTHERAPY; KIDNEY METASTASIS; LUNG TUMOR; LYMPHOMA; MELANOMA; METASTASIS; MULTIPLE MYELOMA; MULTIPLE SCLEROSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; TUMOR ASSOCIATED LEUKOCYTE;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; CYTOKINES; HUMANS; IMMUNOSUPPRESSION; IMMUNOTHERAPY; LYMPHOCYTES, TUMOR-INFILTRATING; NEOPLASMS; PROTEIN-TYROSINE KINASES; T-LYMPHOCYTES, REGULATORY; TUMOR ESCAPE;

EID: 77956678640     PISSN: 08830185     EISSN: 15635244     Source Type: Journal    
DOI: 10.3109/08830185.2010.508854     Document Type: Review

References (189)

1. Pages F, Kirilovsky A, Mlecnik B, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009;27:5944-5951.
2. Al-Shibli KI, Donnem T, Al-Saad S, et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 2008;14:5220-5227.
3. Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-459.
4. 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;102:18538-18543.
5. Kondratiev S, Sabo E, Yakirevich E, et al. Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res 2004;10:4450-4456.
6. Koebel CM, Vermi W, Swann JB, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007;450:903-907.
7. Watson NF, Ramage JM, Madjd Z, et al. Immunosurveillance is active in colorec-tal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis. Int J Cancer 2006;118:6-10.
8. Atkins D, Breuckmann A, Schmahl GE, et al. MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. Int J Cancer 2004;109:265-273.
9. Tourkova IL, Shurin GV, Ferrone S, Shurin MR. Interferon regulatory factor 8 mediates tumor-induced inhibition of antigen processing and presentation by dendritic cells. Cancer Immunol Immunother 2009;58:567-574.
10. Cathro HP, Smolkin ME, Theodorescu D, et al. Relationship between HLA class I antigen processing machinery component expression and the clinicopathologic characteristics of bladder carcinomas. Cancer Immunol Immunother 2010;59:465-472.
11. Dart LL, Smith DM, Meyers CA, et al. Transforming growth factors from a human tumor cell: Characterization of transforming growth factor beta and identification of high molecular weight transforming growth factor alpha. Biochemistry 1985;24:5925-5931.
12. O'Garra A, Stapleton G, Dhar V, et al. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol 1990;2:821-832.
13. Sharma S, Stolina M, Yang SC, et al. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 2003;9:961-968.
14. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 2002;8:793-800.
15. Liu X, Gao JX, Wen J, et al. B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism. J Exp Med 2003;197:1721-1730.
16. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci \USA 2003;100:4712-4717.
17. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunological self-tolerance maintained by activated T-cells expressing Il-2 receptor alpha-chains (Cd25)\-Breakdown of a single mechanism of self-tolerance causes various autoimmune-diseases. J Immunol 1995;155:1151-1164.
18. Strauss L, Bergmann C, Whiteside TL. Human circulating CD4+CD25highFoxp3 +regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol 2009;182:1469-1480.
19. Wang XN, Haniffa MA, Holtick U, et al. Regulatory T-cell suppression of CD8+ T-cell-mediated graft-versus-host reaction requires their presence during priming. Transplantation 2009;88:188-197.
20. Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother 2007;56:271-285.
21. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
22. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
23. Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007;110:2983-2990.
24. Wang J, Ioan-Facsinay A, Van Der Voort EIH, et al. Transient expression of FOXP3 in human activated nonregulatory CD4(+) T cells. Euro J Immunol 2007;37:129-138.
25. Ichihara F, Kono K, Takahashi A, et al. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 2003;9:4404-4408.
26. Ormandy LA, Hillemann T, Wedemeyer H, et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005;65:2457-2464.
27. Karube K, Ohshima K, Tsuchiya T, et al. Expression of FoxP3, a key molecule in CD4(+)CD25(+) regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol 2004;126:81-84.
28. 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;61:4766-4772.
29. Marshall NA, Christie LE, Munro LR, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004;103:1755-1762.
30. Viguier M, Lemaitre 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;173:1444-1453.
31. Curiel TJ, Coukos G, Zou LH, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-949.
32. Balkwill F. Chemokine biology in cancer. Semin Immunol 2003;15:49-55.
33. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood 2002;99:4283-4297.
34. Dhawan P, Richmond A. Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol 2002;72:9-18.
35. Belperio JA, Keane MP, Arenberg DA, et al. CXC chemokines in angiogenesis. J Leukoc Biol 2000;68:1-8.
36. Luan J, Shattuck-Brandt R, Haghnegahdar H, et al. Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. J Leukoc Biol 1997;62:588-597.
37. Takamori H, Oades ZG, Hoch OC, et al. Autocrine growth effect of IL-8 and GROal-pha on a human pancreatic cancer cell line, Capan-1. Pancreas 2000;21:52-56.
38. Berin MC, Eckmann L, Broide DH, Kagnoff MF. Regulated production of the T helper 2-type T-cell chemoattractant TARC by human bronchial epithelial cells in vitro and in human lung xenografts. Am J Respir Cell & Mol Biol 2001;24:382-389.
39. Hagemann T, Wilson J, Burke F, et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol 2006;176:5023-5032.
40. Nakanishi T, Imaizumi K, Hasegawa Y, et al. Expression of macrophage-derived chemokine (MDC)/CCL22 in human lung cancer. Cancer Immunol Immunother 2006;55:1320-1329.
41. Qin XJ, Shi HZ, Deng JM, et al. CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clin Cancer Res 2009;15:2231-2237.
42. Takegawa S, Jin Z, Nakayama T, et al. Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder. Cancer Sci 2008;99:296-302.
43. Maruyama T, Kono K, Izawa S, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Dis Esophagus 2010;23(5):422-429.
44. Gobert M, Treilleux I, Bendriss-Vermare N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 2009;69:2000-2009.
45. 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;122:2286-2293.
46. Cornforth AN, Lee GJ, Fowler AW, et al. Increases in serum TARC/CCL17 levels are associated with progression-free survival in advanced melanoma patients in response to dendritic cell-based immunotherapy. J Clin Immunol 2009;29:657-664.
47. Iellem A, Mariani M, Lang R, et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exper Med 2001;194:847-853.
48. Niens M, Visser L, Nolte IM, et al. Serum chemokine levels in Hodgkin lym-phoma patients: Highly increased levels of CCL17 and CCL22. Br J Haematol 2008;140:527-536.
49. Bernardini G, Hedrick J, Sozzani S, et al. Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor. Eur J Immunol 1998;28:582-588.
50. Hoshino A, Kawamura YI, Yasuhara M, et al. Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions. J Immunol 2007;178:5296-5304.
51. Bottazzi B, Walter S, Govoni D, et al. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 1992;148:1280-1285.
52. Carr MW, Roth SJ, Luther E, et al. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci \USA 1994;91:3652-3656.
53. Metelitsa LS, Wu HW, Wang H, et al. Natural killer T cells infiltrate neuroblas-tomas expressing the chemokine CCL2. J Exp Med 2004;199:1213-1221.
54. Mizutani K, Sud S, McGregor NA, et al. The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment. Neoplasia 2009;11:1235-1242.
55. Li X, Loberg R, Liao J, et al. A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res 2009;69:1685-1692.
56. Cai Z, Chen Q, Chen J, et al. Monocyte chemotactic protein 1 promotes lung cancer-induced bone resorptive lesions in vivo. Neoplasia 2009;11:228-236.
57. Jordan JT, Sun W, Hussain SF, et al. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother 2008;57:123-131.
58. Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev 2010;21(1):41-48.
59. Chavey C, Bibeau F, Gourgou-Bourgade S, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res 2007;9:R15.
60. Vande Broek I, Asosingh K, Vanderkerken K, et al. Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1,-2 and-3. Br J Cancer 2003;88:855-862.
61. Torisu H, Ono M, Kiryu H, et al. Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFalpha and IL-1alpha. Int J Cancer 2000;85:182-188.
62. Phillips RJ, Burdick MD, Lutz M, et al. The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med 2003;167:1676-1686.
63. Schimanski CC, Schwald S, Simiantonaki N, et al. Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res 2005;11:1743-1750.
64. Zou L, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4+CD25 +regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res 2004;64:8451-8455.
65. Grauer OM, Nierkens S, Bennink E, et al. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int J Cancer 2007;121:95-105.
66. Wei S, Kryczek I, Edwards RP, et al. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res 2007;67:7487-7494.
67. Sasada T, Kimura M, Yoshida Y, et al. CD4(+)CD25(+) regulatory T cells in patients with gastrointestinal malignancies\-Possible involvement of regulatory T cells in disease progression. Cancer 2003;98:1089-1099.
68. Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287-296.
69. Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: Induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998;10:1969-1980.
70. Rubtsov YP, Rasmussen JP, Chi EY,et al. RegulatoryTcell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28:546-558.
71. Ise W, Kohyama M, Nutsch KM, et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 2010;11:129-135.
72. Chen C, Rowell EA, Thomas RM, et al. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006;281:36828-36834.
73. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
74. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exper Med 2000;192:295-302.
75. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exper Med 2000;192:303-309.
76. Collins AV, Brodie DW, Gilbert RJ, et al. The interaction properties of costimula-tory molecules revisited. Immunity 2002;17:201-210.
77. Linsley PS, Greene JL, Tan P, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 1992;176:1595-1604.
78. Vandenborre K, Van Gool SW, Kasran A, et al. Interaction of CTLA-4 (CD152) with CD80 or CD86 inhibits human T-cell activation. Immunology 1999;98:413-421.
79. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271-275.
80. Freeman GJ, Gribben JG, Boussiotis VA, et al. Cloningof B7-2: A CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 1993;262:909-911.
81. Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206-1212.
82. Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002;9:1069-1077.
83. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001;194:629-644.
84. Green EA, Gorelik L, McGregor CM, et al. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci \USA 2003;100:10878-10883.
85. Bopp T, Becker C, Klein M, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell mediated suppression. J Exper Med 2007;204:1303-1310.
86. Hoskin DW, Mader JS, Furlong SJ, et al. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells (Review). Int J Oncol 2008;32:527-535.
87. Bodor J, Fehervari Z, Diamond B, Sakaguchi S. ICER/CREM-mediated transcrip-tional attenuation of IL-2 and its role in suppression by regulatory T cells. Eur J Immunol 2007;37:884-895.
88. Oberle N, Eberhardt N, Falk CS, et al. Rapid suppression of cytokine transcription in human CD4+CD25 T cells by CD4+Foxp3+ regulatory T cells: Independence of IL-2 consumption, TGF-beta, and various inhibitors of TCR signaling. J Immunol 2007;179:3578-3587.
89. Bodor J, Habener JF. Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes. J Biol Chem 1998;273:9544-9551.
90. 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.
91. Gondek DC, Lu LF, Quezada SA, et al. Cutting edge: Contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005;174:1783-1786.
92. Kryczek I, Lange A, Mottram P, et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res 2005;65:465-472.
93. Steinbrink K, Wolfl M, Jonuleit H, et al. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 1997;159:4772-4780.
94. Harizi H, Juzan M, Pitard V, et al. Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions. J Immunol 2002;168:2255-2263.
95. Geissmann F, Revy P, Regnault A, et al. TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 1999;162:4567-4575.
96. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-444.
97. Yigit R, Massuger LF, Figdor CG, Torensma R. Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecol Oncol 2010;117:366-372.
98. Sheu BC, Chang WC, Cheng CY, et al. Cytokine regulation networks in the cancer microenvironment. Front Biosci 2008;13:6255-6268.
99. 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;389:737-742.
100. Nakamura K, Kitani A, Fuss I, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834-842.
101. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450:566-569.
102. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257-1265.
103. Jonuleit H, Schmitt E, Schuler G, et al. Induction of interleukin 10-producing, non-proliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000;192:1213-1222.
104. Kryczek I, Wei S, Zou L, et al. Cutting edge: Induction of B7-H4 on APCs through IL-10: Novel suppressive mode for regulatory T cells. J Immunol 2006;177:40-44.
105. De la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD4(+)CD25(+) regulatory T cell function. Euro J Immunol 2004;34:2480-2488.
106. Barthlott T, Moncrieffe H, Veldhoen M, et al. CD25(+)CD4(+) T cells compete with naive CD4(+) T cells for IL-2 and exploit it for the induction of IL-10 production. Int Immunol 2005;17:279-288.
107. Zambricki E, Shigeoka A, Kishimoto H, et al. Signaling T-cell survival and death by IL-2 and IL-15. Am J Transplant 2005;5:2623-2631.
108. McDonald SA, Palmen MJ, Van Rees EP, MacDonald TT. Characterization of the mucosal cell-mediated immune response in IL-2 knockout mice before and after the onset of colitis. Immunology 1997;91:73-80.
109. Yates J, Rovis F, Mitchell P, et al. The maintenance of human CD4+ CD25 +regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppres-sive potency in vitro. Int Immunol 2007;19:785-799.
110. Bayry J, Tchilian EZ, Davies MN, et al. In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination. Proc Natl Acad Sci \USA 2008;105:10221-10226.
111. Andrews G, Jones C, Wreggett KA. An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5. Mol Pharmacol 2008;73:855-867.
112. Kang S, Xie J, Ma S, et al. Targeted knock down of CCL22 and CCL17 by siRNA during DC differentiation and maturation affects the recruitment of T subsets. Immunobiology 2010;215:153-162.
113. Baatar D, Olkhanud P, Newton D, et al. CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors. J Immunol 2007;179:1996-2004.
114. Olkhanud PB, Baatar D, Bodogai M, et al. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 2009;69:5996-6004.
115. Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 2010;28:1591-1598.
116. Ishii T, Ishida T, Utsunomiya A, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res 2010;16:1520-1531.
117. Sebastiani S, Allavena P, Albanesi C, et al. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 2001;166:996-1002.
118. Fridlender ZG, Buchlis G, Kapoor V, et al. CCL2 blockade augments cancer im-munotherapy. Cancer Res 2010;70:109-118.
119. Xia M, Sui Z. Recent developments in CCR2 antagonists. Expert Opin Ther Pat 2009;19:295-303.
120. Haringman JJ, Gerlag DM, Smeets TJ, et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:2387-2392.
121. Horuk R. Chemokine receptor antagonists: Overcoming developmental hurdles. Nat Rev Drug Discov 2009;8:23-33.
122. Azab AH, Runnels JM, Pitsillides C, et al. CXCR4 inhibitor AMD3100 disrupts the interactionof multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 2009;113:4341-4351.
123. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 [E-pub ahead of print].
124. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043-6053.
125. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radio-pharm 2009;24:321-325.
126. 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;120:2723-2733.
127. 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;28:582-592.
128. Gerena-Lewis M, Crawford J, Bonomi P, et al. A Phase II trial of Denileukin Diftitox in patients with previously treated advanced non-small cell lung cancer. Am J Clin Oncol 2009;32:269-273.
129. Cho JS, Hsu JV, Morrison SL. Localized expression of GITR-L in the tumor mi-croenvironment promotes CD8+ T cell dependent anti-tumor immunity. Cancer Immunol Immunother 2009;58:1057-1069.
130. 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;135-142.
131. Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci \USA 2003;100:15059-15064.
132. Sonawane SB, Kim JI, Lee MK, et al. GITR blockade facilitates Treg mediated allograft survival. Transplantation 2009;88:1169-1177.
133. Cohen AD, Diab A, Perales MA, et al. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res 2006;66:4904-4912.
134. Ramirez-Montagut T, Chow A, Hirschhorn-Cymerman D, et al. Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J Immunol 2006;176:6434-6442.
135. Zhou P, L'Italien S, Hodges D, Schebye XM. Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J Immunol 2007;179:7365-7375.
136. Mitsui J, Nishikawa H, Muraoka D, et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res 2010;16:2781-2791.
137. Coe D, Begom S, Addey C, et al. Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol Immunother 2010;59(9):1367-1377.
138. Takeda I, Ine S, Killeen N, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 2004;172:3580-3589.
139. Vu MD, Xiao X, Gao W, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood 2007;110:2501-2510.
140. Kaneko H, Hori T, Yanagita S, et al. Introduction of OX40 ligand into lymphoma cells elicits anti-lymphoma immunity in vivo. Exp Hematol 2005;33:336-343.
141. Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 2008;205:825-839.
142. Yokouchi H, Yamazaki K, Chamoto K, et al. Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. Cancer Sci 2008;99:361-367.
143. Pisters PW, Patel SR. Gastrointestinal stromal tumors: Current management. J Surg Oncol 2010 [E-pub ahead of print].
144. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007;178:1883-1887.
145. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-124.
146. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561-566.
147. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.
148. Beppu K, Jaboine J, Merchant MS, et al. Effect of imatinib mesylate on neurob-lastoma tumorigenesis and vascular endothelial growth factor expression. J Natl Cancer Inst 2004;96:46-55.
149. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacoki-netic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327-337.
150. Roskoski R Jr. Sunitinib: A VEGF and PDGF receptor protein kinase and angio-genesis inhibitor. Biochem Biophys Res Commun 2007;356:323-328.
151. Wang WL, Healy ME, Sattler M, et al. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000;19:3521-3528.
152. Seggewiss R, Lore K, Greiner E, et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 2005;105:2473-2479.
153. Dietz AB, Souan L, Knutson GJ, et al. Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 2004;104:1094-1099.
154. Gu Y, Zhao W, Meng F, et al. Sunitinib impairs the proliferation and function of human peripheral T cell and prevents T-cell-mediated immune response in mice. Clin Immunol 2010;135:55-62.
155. Larmonier N, Janikashvili N, LaCasse CJ, et al. Imatinib mesylate inhibits CD4 +CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL-tumors. J Immunol 2008;181:6955-6963.
156. Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor mi-croenvironment for immune-based cancer therapies. Cancer Res 2009;69:2514-2522.
157. Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009;15:2148-2157.
158. Finke JH, Rini B, Ireland J, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 2008;14:6674-6682.
159. Apostolou I, Sarukhan A, Klein L, and von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002;3:756-763.
160. Degauque N, Lair D, Braudeau C, et al. Development of CD25(-) regulatory T cells following heart transplantation: Evidence for transfer of long-term survival. Euro J Immunol 2007;37:147-156.
161. Shevach EM. CD4(+)CD25(+) suppressor T cells: More questions than answers. Nat Rev Immunol 2002;2:389-400.
162. Kuniyasu Y, Takahashi T, Itoh M, et al. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoreg-ulatory T cell subpopulation. Int Immunol 2000;12:1145-1155.
163. Jiang H, Ware R, Stall A, et al. Murine Cd8(+) T-cells that specifically delete au-tologous Cd4(+) T-cells expressing V-beta-8 Tcr A role of the Q-alpha-1 molecule. Immunity 1995;2:185-194.
164. Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NSF. CD8(+)CD28(-) T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev 2001;182:201-206.
165. Sobhani I, Le Gouvello S. Critical role for CD8+FoxP3+ regulatory T cells in colon cancer immune response in humans. Gut 2009;58:743-744.
166. 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;24:5373-5380.
167. Xu L, Xu W, Qiu S, Xiong S. Enrichment of CCR6(+)Foxp3(+) regulatory T cells in the tumor mass correlates with impaired CD8(+) T cell function and poor prognosis of breast cancer. Clin Immunol 2010;135(3):466-475.
168. 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;11:8326-8331.
169. Li JF, Chu YW, Wang GM, et al. The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int 2009;103:399-405.
170. Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186-192.
171. Suzuki H, Chikazawa N, Tasaka T, et al. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother 2010;59(5):653-661.
172. Loddenkemper C, Schernus M, Noutsias M, et al. In situ analysis of FOXP3 +regulatory T cells in human colorectal cancer. J Transl Med 2006;4:52.
173. Sinicrope FA, Rego RL, Ansell SM, et al. Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gas-troenterology 2009;137:1270-1279.
174. Grabenbauer GG, Lahmer G, Distel L, Niedobitek G. Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 2006;12:3355-3360.
175. de Jong RA, Leffers N, Boezen HM, et al. Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol 2009;114:105-110.
176. 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. Gastroen-terology 2007;132:2328-2339.
177. 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;25:2586-2593.
178. Carreras J, Lopez-Guillermo A, Fox BC, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 2006;108:2957-2964.
179. Kelley TW, Pohlman B, Elson P, His ED. The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression. Am J Clin Pathol 2007;128:958-965.
180. Perrone G, Ruffini PA, Catalano V, et al. Intratumoral FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 2008;44;1875-1882.
181. Shen Z, Zhou S, Wang Y, et al. Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8 +ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol [E-pub ahead of print].
182. Meagher C, Arreaza G, Peters A, et al. CCL4 protects from type 1 diabetes by altering islet beta-cell-targeted inflammatory responses. Diabetes 2007;56:809-817.
183. Yuan Q, Bromley SK, Means TK, et al. CCR4-dependent regulatory T cell function in inflammatory bowel disease. J Exp Med 2007;204:1327-1334.
184. Schnickel GT, Bastani S, Hsieh GR, et al. Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection. J Immunol 2008;180:4714-4721.
185. Chen D, Zhang N, Fu S, et al. CD4+ CD25+ regulatory T-cells inhibit the islet innate immune response and promote islet engraftment. Diabetes 2006;55:1011-1021.
186. Muller M, Carter SL, Hofer MJ, et al. CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. J Immunol 2007;179:2774-2786.
187. Hasegawa H,InoueA, Muraoka M,et al. Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. Arthritis Res Ther 2007;9:R15.
188. Moreira AP, Cavassani KW, Massafera Tristao FS, et al. CCR5-dependent regulatory T cell migration mediates fungal survival and severe immunosuppression. J Immunol 2008;180:3049-3056.
189. Nguyen KD, Fohner A, Booker JD, et al. XCL1 enhances regulatory activities of CD4+ CD25(high) CD127(low/-) T cells in human allergic asthma. J Immunol 2008;181:5386-5395.