Natural and induced T regulatory cells in cancer

Frontiers in Immunology

Volumn 4, Issue JUL, 2013, Pages

  Adeegbe, Dennis O ^a   Nishikawa, Hiroyoshi ^a  

^a OSAKA UNIVERSITY   (Japan)

Author keywords

Cancer; Foxp3; Induced; Interleukin 10; Natural; Transforming growth factor ; Tregs; Tumor

Indexed keywords

CHEMOKINE RECEPTOR CCR; CYCLOPHOSPHAMIDE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; DACLIZUMAB; DENILEUKIN DIFTITOX; GLYCOPROTEIN A REPETITIONS PREDOMINANT; INTERLEUKIN 10; INTERLEUKIN 2; IPILIMUMAB; MEMBRANE PROTEIN; NEUROPILIN 1; PROSTAGLANDIN E2; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TUMOR ANTIGEN; UNCLASSIFIED DRUG; ZINC FINGER PROTEIN;

APOPTOSIS; AUTOIMMUNE DISEASE; CANCER IMMUNOTHERAPY; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL MIGRATION; CLINICAL TRIAL (TOPIC); COLON CARCINOMA; COLORECTAL CANCER; DENDRITIC CELL; GENE; GENE EXPRESSION; HELIOS GENE; HODGKIN DISEASE; HUMAN; IMMUNE RESPONSE; IMMUNOBIOLOGY; INDUCED REGULATORY T LYMPHOCYTE; KIDNEY CARCINOMA; LYMPHOCYTE ACTIVATION GENE 3; NATURAL REGULATORY T LYMPHOCYTE; NEOPLASM; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT;

EID: 84883681998     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00190     Document Type: Review

References (140)

1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol (1995) 155(3):1151-64.
2. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4(4):330-6. doi:10.1038/ni904
3. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol (2003) 4(4):337-42. doi:10.1038/ni909
4. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell (2008) 133(5):775-87. doi:10.1016/j.cell.2008.05.009
5. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity (2009) 30(5):626-35. doi:10.1016/j.immuni
6. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol (2003) 3(3):253-7. doi:10.1038/nri1032
7. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev (2006) 212:28-50. doi:10.1111/j.0105-2896.2006.00420.x
8. Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev (2011) 241(1):241-59. doi:10.1111/j.1600-065X
9. Facciabene A, Motz GT, Coukos G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res (2012) 72(9):2162-71. doi:10.1158/0008-5472.CAN-11-3687
10. Whiteside TL, Schuler P, Schilling B. Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther (2012) 12(10):1383-97. doi:10.1517/14712598.2012.707184
11. Elkord E, Alcantar-Orozco EM, Dovedi SJ, Tran DQ, Hawkins RE, Gilham DE. T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther (2010) 10(11):1573-86. doi:10.1517/14712598.2010.529126
12. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer (2010) 127(4):759-67.
13. Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol (2012) 30:733-58. doi:10.1146/annurev-immunol- 020711-075043
14. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (2003) 299(5609):1057-61. doi:10.1126/science.1079490
15. Wilke CM, Wu K, Zhao E, Wang G, Zou W. Prognostic significance of regulatory T cells in tumor. Int J Cancer (2010) 127(4):748-58. doi:10.1002/ijc.25464
16. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med (2004) 10(9):942-9. doi:10.1038/nm1093
17. Hindley JP, Ferreira C, Jones E, Lauder SN, Ladell K, Wynn KK, et al. Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res (2011) 71(3):736-46. doi:10.1158/0008-5472.CAN-10-1797
18. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med (2005) 202(7):919-29. doi:10.1084/jem.20050463
19. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, et al. Tumor evasion of the immune system by converting CD4+CD25-T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol (2007) 178(5):2883-92.
20. Valzasina B, Piconese S, Guiducci C, Colombo MP. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25-lymphocytes is thymus and proliferation independent. Cancer Res (2006) 66(8):4488-95. doi:10.1158/0008-5472.CAN-05-4217
21. Chattopadhyay S, Mehrotra S, Chhabra A, Hegde U, Mukherji B, Chakraborty NG. Effect of CD4+CD25+ and CD4+CD25-T regulatory cells on the generation of cytolytic T cell response to a self but human tumor-associated epitope in vitro. J Immunol (2006) 176(2):984-90.
22. Kohm AP, McMahon JS, Podojil JR, Begolka WS, DeGutes M, Kasprowicz DJ, et al. Cutting Edge: anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J Immunol (2006) 176(6):3301-5.
23. Gomella LG, Sargent ER, Wade TP, Anglard P, Linehan WM, Kasid A. Expression of transforming growth factor alpha in normal human adult kidney and enhanced expression of transforming growth factors alpha and beta 1 in renal cell carcinoma. Cancer Res (1989) 49(24 Pt 1):6972-5.
24. Zhou G, Levitsky HI. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol (2007) 178(4):2155-62.
25. Seo N, Hayakawa S, Takigawa M, Tokura Y. Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology (2001) 103(4):449-57. doi:10.1046/j.1365-2567.2001.01279.x
26. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood (2004) 103(5):1755-62. doi:10.1182/blood-2003-07-2594
27. Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS. Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol (2004) 173(7):4352-9.
28. Bergmann C, Strauss L, Wang Y, Szczepanski MJ, Lang S, Johnson JT, et al. T regulatory type 1 cells in squamous cell carcinoma of the head and neck: mechanisms of suppression and expansion in advanced disease. Clin Cancer Res (2008) 14(12):3706-15. doi:10.1158/1078-0432.CCR-07-5126
29. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL. Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res (2007) 67(18):8865-73. doi:10.1158/0008-5472.CAN-07-0767
30. Dobrzanski MJ, Rewers-Felkins KA, Samad KA, Quinlin IS, Phillips CA, Robinson W, et al. Immunotherapy with IL-10-and IFN-gamma-producing CD4 effector cells modulate "Natural" and "Inducible" CD4 Treg cell subpopulation levels: observations in four cases of patients with ovarian cancer. Cancer Immunol Immunother (2012) 61(6):839-54. doi:10.1007/s00262-011-1128-x
31. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL. Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol Immunother (2007) 56(9):1429-42. doi:10.1007/s00262-007-0280-9
32. Segal BM, Glass DD, Shevach EM. Cutting Edge: IL-10-producing CD4+ T cells mediate tumor rejection. J Immunol (2002) 168(1):1-4.
33. Vieira PL, Christensen JR, Minaee S, O'Neill EJ, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol (2004) 172(10):5986-93.
34. 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(8):2983-90. doi:10.1182/blood-2007-06-094656
35. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol (2006) 6(4):295-307. doi:10.1038/nri1806
36. Mocellin S, Marincola FM, Young HA. Interleukin-10 and the immune response against cancer: a counterpoint. J Leukoc Biol (2005) 78(5):1043-51. doi:10.1189/jlb.0705358
37. Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity (2007) 27(5):786-800. doi:10.1016/j.immuni.2007.09.010
38. Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, et al. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol (2006) 18(8):1197-209. doi:10.1093/intimm/dxl060
39. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ regulatory cells. J Immunol (2010) 184(7):3433-41. doi:10.4049/jimmunol.0904028
40. Elkord E, Sharma S, Burt DJ, Hawkins RE. Expanded subpopulation of FoxP3+ T regulatory cells in renal cell carcinoma co-express Helios, indicating they could be derived from natural but not induced Tregs. Clin Immunol. (2011) 140(3):218-22. doi:10.1016/j.clim.2011.04.014
41. Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunsi K, et al. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res (2012) 72(17):4351-60. doi:10.1158/0008-5472.CAN-12-0579
42. Wainwright DA, Sengupta S, Han Y, Lesniak MS. Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors. Neuro Oncol (2011) 13(12):1308-23. doi:10.1093/neuonc/nor134
43. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med (2012) 209(10):1723-42. doi:10.1084/jem.20120914
44. Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature (2013) 497(7448):258-62. doi:10.1038/nature12079
45. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS ONE (2011) 6(8):e24226. doi:10.1371/journal.pone.0024226
46. Gottschalk RA, Corse E, Allison JP. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol (2012) 188(3):976-80. doi:10.4049/jimmunol.1102964
47. Verhagen J, Wraith DC. Comment on "Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells". Journal of immunology (2010) 185(12):7129. author reply 30. doi:10.4049/jimmunol.1090105
48. Feuerer M, Hill JA, Kretschmer K, von Boehmer H, Mathis D, Benoist C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad Sci U S A (2010) 107(13):5919-24. doi:10.1073/pnas.1002006107
49. Haribhai D, Lin W, Edwards B, Ziegelbauer J, Salzman NH, Carlson MR, et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J Immunol (2009) 182(6):3461-8. doi:10.4049/jimmunol.0802535
50. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med (2012) 209(10):1713-22. doi:10.1084/jem.20120822
51. Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, et al. LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol (2010) 184(11):6545-51. doi:10.4049/jimmunol.0903879
52. Chen X, Subleski JJ, Kopf H, Howard OM, Mannel DN, Oppenheim JJ. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol (2008) 180(10):6467-71.
53. Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS ONE (2012) 7(2):e30676. doi:10.1371/journal.pone.0030676
54. Strauss L, Bergmann C, Szczepanski MJ, Lang S, Kirkwood JM, Whiteside TL. Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression. J Immunol (2008) 180(5):2967-80.
55. Suresh KG, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP+ CTLA-4+ Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T cell functionality. Cancer Res (2013) 73(8):2435-44. doi:10.1158/0008-5472.CAN-12-3381
56. Yan J, Zhang Y, Zhang JP, Liang J, Li L, Zheng L. Tim-3 expression defines regulatory T cells in human tumors. PLoS ONE (2013) 8(3):e58006. doi:10.1371/journal.pone.0058006
57. Hastings WD, Anderson DE, Kassam N, Koguchi K, Greenfield EA, Kent SC, et al. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol (2009) 39(9):2492-501. doi:10.1002/eji.200939274
58. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A (2009) 106(32):13439-44.
59. Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, et al. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest (2009) 119(11):3311-21.
60. Voo KS, Peng G, Guo Z, Fu T, Li Y, Frappier L, et al. Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation. Cancer Res (2005) 65(4):1577-86. doi:10.1158/0008-5472.CAN-04-2552
61. Fialova A, Partlova S, Sojka L, Hromadkova H, Brtnicky T, Fucikova J, et al. Dynamics of T-cell infiltration during the course of ovarian cancer: the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. Int J Cancer (2013) 132(5):1070-9. doi:10.1002/ijc.27759
62. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity (2009) 30(6):899-911. doi:10.1016/j.immuni.2009.03.019
63. Cheng G, Yuan X, Tsai MS, Podack ER, Yu A, Malek TR. IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatory cells. J Immunol (2012) 189(4):1780-91. doi:10.4049/jimmunol.1103768
64. Wang C, Lee JH, Kim CH. Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch. PLoS ONE (2012) 7(1):e30793. doi:10.1371/journal.pone.0030793
65. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M, et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron (2012): doi:10.1007/s12307-012-0122-y
66. Cretney E, Kallies A, Nutt SL. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol (2013) 34(2):74-80. doi:10.1016/j.it.2012.11.002
67. Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol (2011) 12(4):304-11. doi:10.1038/ni.2006
68. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol (2007) 5(2):e38. doi:10.1371/journal.pbio.0050038
69. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity (2012) 37(5):785-99. doi:10.1016/j.immuni.2012.09.010
70. Sainz-Perez A, Lim A, Lemercier B, Leclerc C. The T-cell receptor repertoire of tumor-infiltrating regulatory T lymphocytes is skewed toward public sequences. Cancer Res (2012) 72(14):3557-69. doi:10.1158/0008-5472.CAN-12-0277
71. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist selfpeptide. Nat Immunol (2001) 2(4):301-6. doi:10.1038/86302
72. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol (2012) 12(3):157-67.
73. Khong HT, Restifo NP. Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol (2002) 3(11):999-1005. doi:10.1038/ni1102-999
74. Nishikawa H, Kato T, Tanida K, Hiasa A, Tawara I, Ikeda H, et al. CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc Natl Acad Sci U S A (2003) 100(19):10902-6. doi:10.1073/pnas.1834479100
75. Nishikawa H, Kato T, Tawara I, Saito K, Ikeda H, Kuribayashi K, et al. Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells. J Exp Med (2005) 201(5):681-6. doi:10.1084/jem.20041959
76. Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity (2004) 20(1):107-18. doi:10.1016/S1074-7613(03)00359-5
77. Wang HY, Peng G, Guo Z, Shevach EM, Wang RF. Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol (2005) 174(5):2661-70.
78. Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S. CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood (2005) 106(3):1008-11. doi:10.1182/blood-2005-02-0607
79. Vence L, Palucka AK, Fay JW, Ito T, Liu YJ, Banchereau J, et al. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci U S A (2007) 104(52):20884-9. doi:10.1073/pnas.0710557105
80. Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med (2012) 209(11):2001-16. doi:10.1084/jem.20111497
81. Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, et al. Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol (2004) 34 (3):623-30. doi:10.1002/eji.200324799
82. Glinka Y, Prud'homme GJ. Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol (2008) 84(1):302-10. doi:10.1189/jlb.0208090
83. Liu J, Zhang N, Li Q, Zhang W, Ke F, Leng Q, et al. Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice. PLoS ONE (2011) 6(4):e19495. doi:10.1371/journal.pone.0019495
84. Schlecker E, Stojanovic A, Eisen C, Quack C, Falk CS, Umansky V, et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol (2012) 189(12):5602-11. doi:10.4049/jimmunol.1201018
85. Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol (2009) 182(3):1746-55.
86. Wei S, Kryczek I, Edwards RP, Zou L, Szeliga W, Banerjee M, et al. Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. Cancer Res (2007) 67(15):7487-94. doi:10.1158/0008-5472.CAN-07-0565
87. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature (2011) 475(7355):226-30. doi:10.1038/nature10169
88. Jaafar F, Righi E, Lindstrom V, Linton C, Nohadani M, Van Noorden S, et al. Correlation of CXCL12 expression and FoxP3+ cell infiltration with human papillomavirus infection and clinicopathological progression of cervical cancer. Am J Pathol (2009) 175(4):1525-35. doi:10.2353/ajpath.2009.090295
89. Svensson H, Olofsson V, Lundin S, Yakkala C, Bjorck S, Borjesson L, et al. Accumulation of CCR4(+)CTLA-4 FOXP3(+)CD25(hi) regulatory T cells in colon adenocarcinomas correlate to reduced activation of conventional T cells. PLoS ONE (2012) 7(2):e30695. doi:10.1371/journal.pone.0030695
90. Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K. Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod (2010) 109 (5):744-52. doi:10.1016/j.tripleo.2009.12.015
91. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, ArfiV, 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(5):2000-9. doi:10.1158/0008-5472.CAN-08-2360
92. Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, et al. Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res (2006) 66(11):5716-22. doi:10.1158/0008-5472.CAN-06-0261
93. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol (2011) 11(2):119-30. doi:10.1038/nri2916
94. Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol (2012) 22(4):327-34. doi:10.1016/j.semcancer.2012.03.004
95. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med (2003) 198(12):1875-86. doi:10.1084/jem.20030152
96. Chen W, Konkel JE. TGF-beta and 'adaptive' Foxp3(+) regulatory T cells. J Mol Cell Biol (2010) 2(1):30-6. doi:10.1093/jmcb/mjp004
97. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25-T cells through Foxp3 induction and down-regulation of Smad7. J Immunol (2004) 172(9):5149-53.
98. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009) 9(3):162-74. doi:10.1038/nri2506
99. Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res (2006) 66(2):1123-31. doi:10.1158/0008-5472.CAN-05-1299
100. Ramos RN, Chin LS, Dos Santos AP, Bergami-Santos PC, Laginha F, Barbuto JA. Monocyte-derived dendritic cells from breast cancer patients are biased to induce CD4+CD25+Foxp3+ regulatory T cells. J Leukoc Biol (2012) 92(3):673-82. doi:10.1189/jlb.0112048
101. Kendal AR, Waldmann H. Infectious tolerance: therapeutic potential. Curr Opin Immunol (2010) 22(5):560-5. doi:10.1016/j.coi
102. Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol (2011) 23(6):424-30. doi:10.1016/j.smim
103. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res (2007) 13(15 Pt 1):4345-54. doi:10.1158/1078-0432.CCR-07-0472
104. Dumitriu IE, Dunbar DR, Howie SE, Sethi T, Gregory CD. Human dendritic cells produce TGF-beta 1 under the influence of lung carcinoma cells and prime the differentiation of CD4+CD25+Foxp3+ regulatory T cells. J Immunol (2009) 182(5):2795-807. doi:10.4049/jimmunol.0712671
105. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med (2003) 9(10):1269-74. doi:10.1038/nm934
106. Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Hacker G, et al. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol (2009) 183(1):145-54. doi:10.4049/jimmunol.0803277
107. Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity (2011) 35(1):109-22. doi:10.1016/j.immuni.2011.03.029
108. Schreiber TH, Wolf D, Bodero M, Podack E. Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. Oncoimmunology (2012) 1(5):642-8. doi:10.4161/onci.20298
109. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother (2011) 60(7):909-18. doi:10.1007/s00262-011-1046-y
110. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med (2007) 204(1):57-63. doi:10.1084/jem.20061852
111. Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood (2009) 113 (15):3546-52. doi:10.1182/blood-2008-07-170274
112. Klages K, Mayer CT, Lahl K, Loddenkemper C, Teng MW, Ngiow SF, et al. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res (2010) 70(20):7788-99. doi:10.1158/0008-5472.CAN-10-1736
113. Teng MW, Swann JB, von Scheidt B, Sharkey J, Zerafa N, McLaughlin N, et al. Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. Cancer Res (2010) 70(7):2665-74. doi:10.1158/0008-5472.CAN-09-1574
114. Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity (2007) 27(1):145-59. doi:10.1016/j.immuni.2007.04.017
115. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol (2013) 171(1):36-45. doi:10.1111/j.1365-2249.2012.04657.x
116. Audia S, Nicolas A, Cathelin D, Larmonier N, Ferrand C, Foucher P, et al. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes. Clin Exp Immunol (2007) 150(3):523-30. doi:10.1111/j.1365-2249.2007.03521.x
117. Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, et al. Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med (2005) 201(10):1591-602. doi:10.1084/jem.20042167
118. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother (2007) 56(5):641-8. doi:10.1007/s00262-006-0225-8
119. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood (2005) 105(7):2862-8. doi:10.1182/blood-2004-06-2410
120. de Vries IJ, Castelli C, Huygens C, Jacobs JF, Stockis J, Schuler-Thurner B, et al. Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Clin Cancer Res (2011) 17(4):841-8. doi:10.1158/1078-0432.CCR-10-2227
121. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med (2012) 18(8):1254-61. doi:10.1038/nm.2883
122. Mougiakakos D, Johansson CC, Kiessling R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood (2009) 113(15):3542-5. doi:10.1182/blood-2008-09-181040
123. Park HJ, Kusnadi A, Lee EJ, Kim WW, Cho BC, Lee IJ, et al. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol (2012) 278(1-2):76-83. doi:10.1016/j.cellimm.2012.07.001
124. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A (2010) 107(9):4275-80. doi:10.1073/pnas.0915174107
125. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity (2002) 16(2):311-23. doi:10.1016/S1074-7613(02)00280-7
126. Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE (2010) 5(5):e10436. doi:10.1371/journal.pone.0010436
127. Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumorinfiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med (2005) 202(7):885-91. doi:10.1084/jem.20050940
128. Mitsui J, Nishikawa H, Muraoka D, Wang L, Noguchi T, Sato E, et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res (2010) 16(10):2781-91. doi:10.1158/1078-0432.CCR-09-3243
129. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363(8):711-23. doi:10.1056/NEJMoa1003466
130. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, et al. Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem (2010) 285(10):7176-86. doi:10.1074/jbc. M109.047423
131. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson JT, et al. Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem (2010) 285(36):27571-80. doi:10.1074/jbc. M110.127100
132. Whiteside TL, Mandapathil M, Schuler P. The role of the adenosinergic pathway in immunosuppression mediated by human regulatory T cells (Treg). Curr Med Chem (2011) 18(34):5217-23. doi:10.2174/092986711798184334
133. Conroy H, Galvin KC, Higgins SC, Mills KH. Gene silencing of TGF-beta1 enhances antitumor immunity induced with a dendritic cell vaccine by reducing tumorassociated regulatory T cells. Cancer Immunol Immunother (2012) 61(3):425-31. doi:10.1007/s00262-011-1188-y
134. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol (2007) 8(2):191-7. doi:10.1038/ni1428
135. Sakaguchi S, Powrie F, RansohoffRM. Re-establishing immunological self-tolerance in autoimmune disease. Nat Med (2012) 18(1):54-8. doi:10.1038/nm0412-630a
136. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, et al. gp100 Peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med (2011) 364(22):2119-27. doi:10.1056/NEJMoa1012863
137. Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res (2007) 13(21):6301-11. doi:10.1158/1078-0432.CCR-07-1403
138. Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Lenzner DE, Jackson EK, et al. Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res (2009) 15(20):6348-57. doi:10.1158/1078-0432.CCR-09-1143
139. Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A, et al. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res (2009) 15(10):3325-32. doi:10.1158/1078-0432.CCR-08-3010
140. Geiger TL, Tauro S. Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function. Hum Immunol (2012) 73(3):232-9. doi:10.1016/j.humimm.2011.12.012