Cellular immune responses towards regulatory cells

Danish Medical Journal

Volumn 63, Issue 1, 2016, Pages 1-21

  Larsen, Stine Kiær ^a  

^a GENTOFTE UNIVERSITY HOSPITAL   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; AZACITIDINE; CETUXIMAB; CHEMOKINE RECEPTOR CCR4; CYCLOPHOSPHAMIDE; DACARBAZINE; DECITABINE; DOXORUBICIN; FLUOROURACIL; GAMMA INTERFERON; GEMCITABINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 2; IPILIMUMAB; MACROPHAGE DERIVED CHEMOKINE; METHOTREXATE; MITOMYCIN; OXALIPLATIN; PACLITAXEL; RITUXIMAB; SIPULEUCEL T; T LYMPHOCYTE RECEPTOR; TOSITUMOMAB; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VINBLASTINE; VINCRISTINE;

ADOPTIVE TRANSFER; APOPTOSIS; ARTICLE; B LYMPHOCYTE; CANCER CHEMOTHERAPY; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CD3+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; HUMAN; IMMUNOSURVEILLANCE; KIDNEY CARCINOMA; METASTATIC MELANOMA; NATURAL KILLER CELL; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR GROWTH; TUMOR MICROENVIRONMENT; IMMUNOLOGICAL TECHNIQUE; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASMS; PHYSIOLOGY; PROCEDURES;

HUMANS; IMMUNITY, CELLULAR; IMMUNOLOGIC TECHNIQUES; IMMUNOTHERAPY; NEOPLASMS; T-LYMPHOCYTES, REGULATORY; TUMOR MICROENVIRONMENT;

EID: 84956956190     PISSN: None     EISSN: 22451919     Source Type: Journal    
DOI: None     Document Type: Article

References (207)

1. D. Hanahan and R. Weinberg, “The hallmarks of cancer, ” Cell, vol. 100, pp. 57-70, 2000.
2. D. Hanahan and R. Weinberg, “Hallmarks of cancer:the next generation., ” Cell, vol. 144, no. 5, pp. 646-74, Mar. 2011.
3. R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer immunoediting:integrating immunity’s roles in cancersuppression and promotion., ” Science, vol. 331, no. 6024, pp. 1565-70, Mar. 2011.
4. S. M. Burnet, “Cancer - a biological approach, ” Br. Med. J., no. April 6, pp. 779-786, 1957.
5. L. Old and E. Boyse, “Immunology of experimental tumors, ”Annu. Rev. Med., vol. 15, no. September, pp. 167-186, 1964.
6. G. Dunn, A. Bruce, and H. Ikeda, “Cancer immunoediting:from immunosurveillance to tumor escape, ” Nat. Immunol., vol. 3, no. 11, pp. 991-998, 2002.
7. J. Galon, A. Costes, F. Sanchez-cabo, A. Kirilovsky, C. Lagorce-pagès, M. Tosolini, M. Camus, A. Berger, F. Zinzindohoué, P. Bruneval, P. Cugnenc, Z. Trajanoski, H. Fridman, and F. Pagès, “Type, Density, and LocationPredict Clinical Outcome of Immune Tumors Cells WithinHuman Colorectal,” Science (80)., vol. 313, pp. 1960-64, 2006.
8. L. Zhang, J. R. Conejo-Garcia, D. Katsaros, P. Gimotty, M. Massobrio, G. Regnani, A. Makrigiannakis, H. Gray, K. Schlienger, M. N. Liebman, S. C. Rubin, and G. Coukos, “Intratumoral T cells, recurrence, and survival in epithelialovarian cancer., ” N. Engl. J. Med., vol. 348, no. 3, pp. 203-13, Jan. 2003.
9. F. J. Tefany, R. Barnetson, G. Halliday, S. McCarthy, and W. McCarthy, “Immunocytochemical analysis of the cellularinfiltrate in primary regressing and non-regressingmalignant melanoma, ” J. Invest. Dermatol., vol. 97, no. 2, pp. 197-202, 1991.
10. W. H. Fridman, F. Pagès, C. Sautès-Fridman, and J. Galon, “The immune contexture in human tumours: impacton clinical outcome., ” Nat. Rev. Cancer, vol. 12, no. 4, pp. 298-306, Apr. 2012.
11. M. D. Vesely, M. H. Kershaw, R. D. Schreiber, and M. J. Smyth, “Natural innate and adaptive immunity to cancer., ”Annu. Rev. Immunol., vol. 29, pp. 235-71, Jan. 2011.
12. P. -H. Zahl, P. C. Gøtzsche, and J. Mæhlen, “Natural historyof breast cancers detected in the Swedish mammographyscreening programme: a cohort study., ” LancetOncol., vol. 12, no. 12, pp. 1118-24, Nov. 2011.
13. L. Ferradini, A. Mackensen, C. Genevee, J. Bosq, P. Duvillard, M. Avril, and T. Hercend, “Analysis of T cellreceptor variability in tumor-infiltrating lymphocytesfrom a human regressive melanoma, ” J. Clin. Investig., vol. 91, pp. 1183-1190, 1993.
14. E. Zorn and T. Hercend, “A natural cytotoxic T cell responsein a spontaneously regressing human melanomatargets a neoantigen resulting from a somatic point mutation., ”Eur. J. Immunol., vol. 29, no. 2, pp. 592-601, Feb. 1999.
15. F. Moloney and H. Comber, “A population-based studyof skin cancer incidence and prevalence in renal transplantrecipients, ” Br. J. …, vol. 154, pp. 498-504, 2006.
16. G. D. Kirk, C. Merlo, P. O’ Driscoll, S. H. Mehta, N. Galai, D. Vlahov, J. Samet, and E. Engels, “HIV infection is associatedwith an increased risk for lung cancer, independentof smoking., ” Clin. Infect. Dis., vol. 45, no. 1, pp. 103-10, Jul. 2007.
17. M. DuPage, C. Mazumdar, L. M. Schmidt, A. F. Cheung, and T. Jacks, “Expression of tumour-specific antigensunderlies cancer immunoediting., ” Nature, vol. 482, no. 7385, pp. 405-9, Feb. 2012.
18. H. Matsushita, M. D. Vesely, D. C. Koboldt, C. G. Rickert, R. Uppaluri, V. J. Magrini, C. D. Arthur, J. M. White, Y. -S. Chen, L. K. Shea, J. Hundal, M. C. Wendl, R. Demeter, T. Wylie, J. P. Allison, M. J. Smyth, L. J. Old, E. R. Mardis, and R. D. Schreiber, “Cancer exome analysis reveals a Tcell-dependent mechanism of cancer immunoediting., ”Nature, vol. 482, no. 7385, pp. 400-4, Feb. 2012.
19. M. Davis and P. Bjorkman, “T-cell antigen receptorgenes and T-cell recognition, ” Nature, vol. 334, no. 4AUGUST, pp. 395-402, 1988.
20. B. Kyewski and L. Klein, “A central role for central tolerance., ”Annu. Rev. Immunol., vol. 24, pp. 571-606, Jan. 2006.
21. V. Appay, R. W. van Lier, F. Sallusto, and M. Roederer, “Phenotype and function of human T lymphocyte subsets:consensus and issues., ” Cytometry. A, vol. 73, no. 11, pp. 975-83, Nov. 2008.
22. T. Pentcheva-Hoang, E. Corse, and J. P. Allison, “Negativeregulators of T-cell activation: potential targets fortherapeutic intervention in cancer, autoimmune disease, and persistent infections., ” Immunol. Rev., vol. 229, no. 1, pp. 67-87, May 2009.
23. T. N. Golovina and R. H. Vonderheide, “Regulatory TCells, ” Cancer J., vol. 16, no. 4, pp. 342-347, 2010.
24. M. Sznol and L. Chen, “Antagonist antibodies to PD-1and B7-H1 (PD-L1) in the treatment of advanced humancancer., ” Clin. Cancer Res., vol. 19, no. 5, pp. 1021-34, Mar. 2013.
25. M. H. Andersen and D. Schrama, “Cytotoxic T Cells, ” J. Invest. Dermatol., vol. 126, no. April 2005, pp. 32-41, 2006.
26. P. J. Bjorkman, M. A. Saper, B. Samraoui, W. S. Bennett, L. Strominger, D. C. Wiley, and E. Alerts, “Pillars Article :Structure of the human class I, ” Nature, vol. 329, no. 8OCTOBER, pp. 506-512, 1987.
27. J. M. Vyas, A. G. Van der Veen, and H. L. Ploegh, “Theknown unknowns of antigen processing and presentation., ”Nat. Rev. Immunol., vol. 8, no. 8, pp. 607-18, Aug. 2008.
28. P. van der Bruggen, C. Traversari, P. Chomez, C. Lurquin, E. De Plaen, B. J. Van den Eynde, A. Knuth, and T. Boon, “A gene encoding an antigen recognized by cytolytic Tlymphocytes on a human melanoma., ” Science (80-.)., vol. 254, no. 5038, pp. 2643-47, Mar. 1991.
29. N. Vigneron, V. Stroobant, B. J. Van den Eynde, and P. van der Bruggen, “Database of T cell-defined humantumor antigens: the 2013 update., ” Cancer Immun., vol. 13, no. July, p. 15, Jan. 2013.
30. S. Kiaer Larsen, I. Marie Svane, P. thor Straten, and M. Hald Andersen, “Therapeutic Cancer Vaccines, ” Curr. Cancer Ther. Rev., vol. 6, no. 2, pp. 163-174, May 2010.
31. H. Rammensee, J. Bachmann, N. P. Emmerich, O. aBachor, and S. Stevanović, “SYFPEITHI: database forMHC ligands and peptide motifs., ” Immunogenetics, vol. 50, no. 3-4, pp. 213-9 (Access via www.syfpetihi.de), Nov. 1999.
32. J. C. Becker, M. H. Andersen, D. Schrama, and P. ThorStraten, “Immune-suppressive properties of the tumormicroenvironment., ” Cancer Immunol. Immunother., vol. 62, no. 7, pp. 1137-48, Jul. 2013.
33. T. F. Gajewski, S. -R. Woo, Y. Zha, R. Spaapen, Y. Zheng, L. Corrales, and S. Spranger, “Cancer immunotherapystrategies based on overcoming barriers within the tumormicroenvironment., ” Curr. Opin. Immunol., vol. 25, no. 2, pp. 268-76, Apr. 2013.
34. S. P. Kerkar and N. P. Restifo, “Cellular constituents ofimmune escape within the tumor microenvironment., ”Cancer Res., vol. 72, no. 13, pp. 3125-30, Jul. 2012.
35. S. Spranger, R. M. Spaapen, Y. Zha, J. Williams, Y. Meng, T. T. Ha, and T. F. Gajewski, “Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor MicroenvironmentIs Driven by CD8+ T Cells, ” Sci. Transl. Med., vol. 5, no. 200, pp. 200ra116-200ra116, Aug. 2013.
36. C. Devaud, L. B. John, J. Westwood, P. K. Darcy, and M. H. Kershaw, “Immune modulation of the tumor microenvironmentfor enhancing cancer immunotherapy., ”Oncoimmunology, vol. 2, no. 8, p. e25961, Aug. 2013.
37. A. L. Mellor and D. H. Munn, “IDO expression by dendriticcells: tolerance and tryptophan catabolism., ” Nat. Rev. Immunol., vol. 4, no. 10, pp. 762-74, Oct. 2004.
38. F. Fallarino, U. Grohmann, S. You, B. C. Mcgrath, D. R. Cavener, C. Vacca, C. Orabona, R. Bianchi, M. L. Belladonna, C. Volpi, P. Santamaria, M. C. Fioretti, and P. Puccetti, “The combined effects of tryptophan starvationcatabolites down-regulate T cell receptor zeta-Chain and Induce a Regulatory Phenotype in Naive TCells, ” J. Immunol., vol. 176, pp. 6752-61, 2006.
39. A. Curti, S. Pandolfi, B. Valzasina, M. Aluigi, A. Isidori, E. Ferri, V. Salvestrini, G. Bonanno, S. Rutella, I. Durelli, A. L. Horenstein, F. Fiore, M. Massaia, M. P. Colombo, M. Baccarani, and R. M. Lemoli, “Modulation of tryptophancatabolism by human leukemic cells results in the conversionof CD25- into CD25+ T regulatory cells., ” Blood, vol. 109, no. 7, pp. 2871-7, Apr. 2007.
40. M. D. Sharma, B. Baban, P. Chandler, D. Hou, N. Singh, H. Yagita, M. Azuma, B. R. Blazar, A. L. Mellor, and D. H. Munn, “Plasmacytoid dendritic cells from mouse tumordraininglymph nodes directly activate mature Tregs viaindoleamine 2, 3-dioxygenase, ” J. Clin. Invest., vol. 117, no. 9, pp. 2570-2582, 2007.
41. V. Umansky and A. Sevko, “Tumor microenvironmentand myeloid-derived suppressor cells., ” Cancer Microenviron., vol. 6, no. 2, pp. 169-77, Aug. 2013.
42. S. Ostrand-Rosenberg, Myeloid-derived suppressorcells: more mechanisms for inhibiting antitumor immunity, Cancer Immunol. Immunother., vol. 59, no. October 2009, pp. 1593-1600, 2010.
43. J. Yu, W. Du, F. Yan, Y. Wang, H. Li, S. Cao, W. Yu, C. Shen, J. Liu, and X. Ren, “Myeloid-derived suppressorcells suppress antitumor immune responses throughIDO expression and correlate with lymph node metastasisin patients with breast cancer., ” J. Immunol., vol. 190, no. 7, pp. 3783-97, Apr. 2013.
44. B. Hoechst, L. Ormandy, M. Ballmaier, F. Lehner, C. Krüger, M. P. Manns, T. F. Greten, and F. Korangy, “ANew Population of Myeloid-Derived Suppressor Cells inHepatocellular Carcinoma Patients InducesCD4+CD25+Foxp3+ T cells, ” Gastroenterology, vol. 135, no. 1, pp. 234-43, Jul. 2008.
45. R. K. Gershon and K. Kondo, “Cell interactions in the inductionof tolerance: the role of thymic lymphocytes.,” Immunology, vol. 18, no. 5, pp. 723-37, May 1970.
46. S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, and M. Toda, “Immunologic Self-Tolerance Maintained by ActivatedT cells Expressing IL-2 Receptor a-chains (CD25), ”J. Immunol., vol. 155, no. 3, pp. 1151-64, 1995.
47. M. K. Levings, R. Sangregorio, and M. G. Roncarolo, “Human cd25(+)cd4(+) t regulatory cells suppress naiveand memory T cell proliferation and can be expanded invitro without loss of function., ” J. Exp. Med., vol. 193, no. 11, pp. 1295-302, Jun. 2001.
48. L. S. Taams, J. Smith, M. H. Rustin, M. Salmon, L. W. Poulter, and N. Akbar, “Human anergic/suppressiveCD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population.,” Eur. J. Immunol., vol. 31, no. 4, pp. 1122-31, Apr. 2001.
49. H. Jonuleit, E. Schmitt, M. Stassen, A Tuettenberg, J. Knop, and H. Enk, “Identification and functional characterizationof human CD4(+)CD25(+) T cells with regulatoryproperties isolated from peripheral blood.,” J. Exp. Med., vol. 193, no. 11, pp. 1285-94, Jun. 2001.
50. L. Stephens and C. Mottet, “Human CD4+ CD25+ thymocytesand peripheral T cells have immune suppressiveactivity in vitro, ” Eur. J. Immunol., vol. 31, pp. 1247-1254, 2001.
51. D. Dieckmann, H. Plottner, S. Berchtold, T. Berger, and G. Schuler, “Ex vivo isolation and characterization ofCD4(+)CD25(+) T cells with regulatory properties fromhuman blood., ” J. Exp. Med., vol. 193, no. 11, pp. 1303-10, Jun. 2001.
52. S. Sakaguchi, “Naturally arising Foxp3-expressingCD25+CD4+ regulatory T cells in immunological toleranceto self and non-self.,” Nat. Immunol., vol. 6, no. 4, pp. 345-52, Apr. 2005.
53. C. -S. Hsieh, H. -M. Lee, and C. -W. J. Lio, “Selection ofregulatory T cells in the thymus.,” Nat. Rev. Immunol., vol. 12, no. 3, pp. 157-67, Mar. 2012.
54. S. A. Quezada, K. S. Peggs, T. R. Simpson, and J. P. Allison, “Shifting the equilibrium in cancer immunoediting:from tumor tolerance to eradication.,” Immunol. Rev., vol. 241, no. 1, pp. 104-18, May 2011.
55. C. Ménétrier-Caux, T. Curiel, J. Faget, M. Manuel, C. Caux, and W. Zou, “Targeting regulatory T cells.,” Target. Oncol., vol. 7, no. 1, pp. 15-28, Mar. 2012.
56. A. V Bazhin, S. Kahnert, S. Kimpfler, D. Schadendorf, and V. Umansky, “Distinct metabolism of cyclic adenosinemonophosphate in regulatory and helper CD4+ T cells.,” Mol. Immunol., vol. 47, no. 4, pp. 678-84, Jan. 2010.
57. H. Kuipers, F. Muskens, M. Willart, D. Hijdra, F. B. J. vanAssema, A. J. Coyle, H. C. Hoogsteden, and B. N. Lambrecht, “Contribution of the PD-1 ligands/PD-1 signalingpathway to dendritic cell-mediated CD4+ T cell activation., ” Eur. J. Immunol., vol. 36, no. 9, pp. 2472-82, Sep. 2006.
58. D. Vignali, L. Collison, and C. Workman, “How regulatoryT cells work, ” Nat. Rev. Immunol., vol. 8, no. 7, pp. 523-532, 2008.
59. A. Y. Rudensky, “Regulatory T cells and Foxp3., ” Immunol. Rev., vol. 241, no. 1, pp. 260-8, May 2011.
60. R. S. Wildin, F. Ramsdell, J. Peake, F. Faravelli, J. L. Casanova, N. Buist, E. Levy-Lahad, M. Mazzella, O. Goulet, L. Perroni, F. D. Bricarelli, G. Byrne, M. McEuen, S. Proll, M. Appleby, and M. E. Brunkow, “X-linked neonatal diabetesmellitus, enteropathy and endocrinopathy syndromeis the human equivalent of mouse scurfy., ” Nat. Genet., vol. 27, no. 1, pp. 18-20, Jan. 2001.
61. C. L. Bennett, J. Christie, F. Ramsdell, M. E. Brunkow, P. Ferguson, L. Whitesell, T. Kelly, F. Saulsbury, P. Chance, and H. Ochs, “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) iscaused by mutations of FOXP3, ” Nat. Genet., vol. 27, no. january, pp. 20-21, 2001.
62. S. S. Myatt and E. W. -F. Lam, “The emerging roles offorkhead box (Fox) proteins in cancer., ” Nat. Rev. Cancer, vol. 7, no. 11, pp. 847-59, Nov. 2007.
63. M. Redpath, B. Xu, L. C. van Kempen, and A. Spatz, “Thedual role of the X-linked FoxP3 gene in human cancers., ”Mol. Oncol., vol. 5, no. 2, pp. 156-63, Apr. 2011.
64. Y. Zheng, S. Z. Josefowicz, A. Kas, T. -T. Chu, M. Gavin, and A. Y. Rudensky, “Genome-wide analysis of Foxp3target genes in developing and mature regulatory Tcells., ” Nature, vol. 445, no. 7130, pp. 936-40, Feb. 2007.
65. T. Magg, J. Mannert, J. W. Ellwart, I. Schmid, and M. H. Albert, “Subcellular localization of FOXP3 in human regulatoryand nonregulatory T cells.,” Eur. J. Immunol., vol. 42, no. 6, pp. 1627-38, Jun. 2012.
66. M. Walker and D. Kasprowicz, “Induction of FoxP3 andacquisition of T regulatory activity by stimulated humanCD4+ CD25-T cells,” J. Clin. Investig., vol. 112, no. 9, pp. 1437-1443, 2003.
67. A. N. McMurchy, J. Gillies, M. C. Gizzi, M. Riba, J. M. Garcia-Manteiga, D. Cittaro, D. Lazarevic, S. Di Nunzio, I. S. Piras, A. Bulfone, M. G. Roncarolo, E. Stupka, R. Bacchetta, and M. K.Levings, “A novel function for FOXP3in humans: intrinsic regulation of conventional T cells., ”Blood, vol. 121, no. 8, pp. 1265-75, Feb. 2013.
68. E. Capriotti, E. C. Vonderheid, C. J. Thoburn, M. Wasik, D. W. Bahler, and A. D. Hess, “Expression of T-plastin, FoxP3 and other tumor-associated markers by leukemicT-cells of cutaneous T-cell lymphoma., ” Leuk. Lymphoma, vol. 49, no. 6, pp. 1190-201, Jun. 2008.
69. S. Hinz, L. Pagerols-Raluy, H. -H. Oberg, O. Ammerpohl, S. Grüssel, B. Sipos, R. Grützmann, C. Pilarsky, H. Ungefroren, H. -D. Saeger, G. Klöppel, D. Kabelitz, and H. Kalthoff, “Foxp3 expression in pancreatic carcinoma cells asa novel mechanism of immune evasion in cancer., ” CancerRes., vol. 67, no. 17, pp. 8344-50, Sep. 2007.
70. A. Merlo, P. Casalini, M. L. Carcangiu, C. Malventano, T. Triulzi, S. Mènard, E. Tagliabue, and A. Balsari, “FOXP3expression and overall survival in breast cancer., ” J. Clin. Oncol., vol. 27, no. 11, pp. 1746-52, Apr. 2009.
71. S. Nair, A. J. Aldrich, E. McDonnell, Q. Cheng, A. Aggarwal, P. Patel, M. M. Williams, D. Boczkowski, H. K. Lyerly, M. Morse, and G. R. Devi, “Immunologic targetingof FOXP3 in inflammatory breast cancer cells.,” PLoSOne, vol. 8, no. 1, p. e53150, Jan. 2013.
72. C. Ugolini, R. Elisei, A. Proietti, and S. Pelliccioni, “FoxP3expression in papillary thyroid carcinoma: a possible resistancebiomarker to 131-iodine treatment, ” Thyroid, vol. August 5, pp. 1-23, 2013.
73. K. Karube, K. Ohshima, T. Tsuchiya, T. Yamaguchi, R. Kawano, J. Suzumiya, A. Utsunomiya, M. Harada, and M. Kikuchi, “Expression of FoxP3, a key molecule inCD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells.,” Br. J. Haematol., vol. 126, no. 1, pp. 81-4, Jul. 2004.
74. E. Y. Woo, C. S. Chu, T. J. Goletz, K. Schlienger, H. Yeh, G. Coukos, S. C. Rubin, L. R. Kaiser, and C. H. June, “RegulatoryCD4(+)CD25(+) T cells in tumors from patients withearly-stage non-small cell lung cancer and late-stageovarian cancer., ” Cancer Res., vol. 61, no. 12, pp. 4766-72, Jun. 2001.
75. L. Ormandy, T. Hillemann, and H. Wedemeyer, “Increasedpopulations of regulatory T cells in peripheralblood of patients with hepatocellular carcinoma, ” CancerRes., vol. 65, no. 6, pp. 2457-2464, 2005.
76. E. Y. Woo, C. S. Chu, T. J. Goletz, K. Schlienger, H. Yeh, G. Coukos, S. C. Rubin, L. R. Kaiser, and C. H. June, “RegulatoryCD4 + CD25 + T Cells in Tumors from Patients withEarly-Stage Non-Small Cell Lung Cancer and Late-StageOvarian Cancer, ” pp. 4766-4772, 2001.
77. L. A. Ormandy, T. Hillemann, H. Wedemeyer, M. P. Manns, T. F. Greten, and F. Korangy, “Increased Populationsof Regulatory T Cells in Peripheral Blood of Patientswith Hepatocellular Carcinoma Increased Populationsof Regulatory T Cells in Peripheral Blood ofPatients with Hepatocellular Carcinoma, ” Cancer Res., vol. 65, pp. 2457-2464, 2005.
78. T. Schneider, S. Kimpfler, A. Warth, P. Schnabel, H. Dienemann, D. Schadendorf, H. Hoffmann, and V. Umansky, “Foxp3+ regulatory T cells and natural killercells distinctly infiltrate primary tumors and draininglymph nodes in pulmonary adenocarcinoma, ” J. Thorac. Oncol., vol. 6, no. 3, pp. 432-438, 2011.
79. U. K. Liyanage, T. T. Moore, H. -G. Joo, Y. Tanaka, V. Herrmann, G. Doherty, J. Drebin, S. M. Strasberg, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan, “Prevalenceof regulatory T cells is increased in peripheralblood and tumor microenvironment of patients withpancreas or breast adenocarcinoma., ” J. Immunol., vol. 169, no. 5, pp. 2756-61, Sep. 2002.
80. A. Wolf, D. Wolf, M. Steurer, and G. Gastl, “Increase ofregulatory T cells in the peripheral blood of cancer patients, ” Clin. cancer Res., vol. 9, pp. 606-612, 2003.
81. N. A. Marshall, L. E. Christie, L. R. Munro, D. J. Culligan, P. W. Johnston, R. N. Barker, and M. Vickers, “Immunosuppressiveregulatory T cells are abundant in the reactivelymphocytes of Hodgkin lymphoma.,” Blood, vol. 103, no. 5, pp. 1755-62, Mar. 2004.
82. F. Ichihara, K. Kono, and A. Takahashi, “Increased populationsof regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric andesophageal cancers,” Clin. cancer Res., vol. 9, pp. 4404-4408, 2003.
83. T. Sasada, M. Kimura, Y. Yoshida, M. Kanai, and A. Takabayashi, “CD4+ CD25+ Regulatory T Cells in Patientswith Gastrointestinal Malignancies - Possible Involvementof Regulatory T Cells in Disease Progression, ” Cancer, vol. 98, no. 5, pp. 1089-1099, 2003.
84. C. P. Gray, P. Arosio, and P. Hersey, “Association of IncreasedLevels of Heavy-Chain Ferritin with IncreasedCD4 + CD25 + Regulatory T-Cell Levels in Patients withMelanoma, ” Clin. cancer Res., vol. 9, pp. 2551-2559, 2003.
85. M. Viguier, F. Lemaître, and O. Verola, “Foxp3 expressingCD4+ CD25high regulatory T cells are overrepresentedin human metastatic melanoma lymph nodesand inhibit the function of infiltrating T cells, ” J. Immunol., vol. 173, pp. 1444-53, 2004.
86. T. J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J. R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M. L. Disis, K. L. Knutson, L. Chen, and W. Zou, “Specific recruitment of regulatoryT cells in ovarian carcinoma fosters immune privilegeand predicts reduced survival., ” Nat. Med., vol. 10, no. 9, pp. 942-9, Sep. 2004.
87. E. Sato, S. H. Olson, J. Ahn, B. Bundy, H. Nishikawa, F. Qian, A. A. Jungbluth, D. Frosina, S. Gnjatic, C. Ambrosone, J. Kepner, T. Odunsi, G. Ritter, S. Lele, Y. Chen, H. Ohtani, L. J. Old, and K. Odunsi, “Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/ regulatoryT cell ratio are associated with favorable prognosisin ovarian cancer, ” Proc. Natl. Acad. Sci. U. S. A., vol. 102, no. 51, pp. 18538-43, 2005.
88. K. Kono, H. Kawaida, A. Takahashi, H. Sugai, K. Mimura, N. Miyagawa, H. Omata, and H. Fujii, “CD4(+)CD25highregulatory T cells increase with tumor stage in patientswith gastric and esophageal cancers.,” Cancer Immunol. Immunother., vol. 55, no. 9, pp. 1064-71, Sep. 2006.
89. S. Zhou, S. Xu, H. Tao, Z. Zhen, G. Chen, Z. Zhang, and Y. Yang, “CCR7 Expression and Intratumoral FOXP3(+)Regulatory T Cells are Correlated with Overall Survivaland Lymph Node Metastasis in Gastric Cancer.,” PLoSOne, vol. 8, no. 9, p. e74430, Jan. 2013.
90. N. Hiraoka, K. Onozato, T. Kosuge, and S. Hirohashi, “Prevalence of FOXP3+ regulatory T cells increases duringthe progression of pancreatic ductal adenocarcinomaand its premalignant lesions., ” Clin. Cancer Res., vol. 12, no. 18, pp. 5423-34, Sep. 2006.
91. R. P. Petersen, M. J. Campa, J. Sperlazza, D. Conlon, M. -B. Joshi, D. H. Harpole, and E. F. Patz, “Tumor infiltratingFoxp3+ regulatory T-cells are associated with recurrencein pathologic stage I NSCLC patients., ” Cancer, vol. 107, no. 12, pp. 2866-72, Dec. 2006.
92. Q. Gao, S. -J. Qiu, J. Fan, J. Zhou, X. -Y. Wang, Y. -S. Xiao, Y. Xu, Y. -W. Li, and Z. -Y. Tang, “Intratumoral balance ofregulatory and cytotoxic T cells is associated with prognosisof hepatocellular carcinoma after resection., ” J. Clin. Oncol., vol. 25, no. 18, pp. 2586-93, Jun. 2007.
93. F. Liotta, M. Gacci, F. Frosali, V. Querci, G. Vittori, A. Lapini, V. Santarlasci, S. Serni, L. Cosmi, L. Maggi, R. Angeli, B. Mazzinghi, P. Romagnani, E. Maggi, M. Carini, S. Romagnani, and F. Annunziato, “Frequency of regulatoryT cells in peripheral blood and in tumour-infiltratinglymphocytes correlates with poor prognosis in renal cellcarcinoma., ” BJU Int., vol. 107, no. 9, pp. 1500-6, May2011.
94. M. Gobert, I. Treilleux, N. Bendriss-Vermare, T. Bachelot, S. Goddard-Leon, V. Arfi, C. Biota, A. C. Doffin, I. Durand, D. Olive, S. Perez, N. Pasqual, C. Faure, I. Ray-Coquard, A. Puisieux, C. Caux, J. -Y. Blay, and C. Ménétrier-Caux, “Regulatory T cells recruited throughCCL22/CCR4 are selectively activated in lymphoid infiltratessurrounding primary breast tumors and lead toan adverse clinical outcome., ” Cancer Res., vol. 69, no. 5, pp. 2000-9, Mar. 2009.
95. X. Yao, M. Ahmadzadeh, Y. -C. Lu, D. J. Liewehr, M. E. Dudley, F. Liu, D. S. Schrump, S. M. Steinberg, S. A. Rosenberg, and P. F. Robbins, “Levels of peripheralCD4(+)FoxP3(+) regulatory T cells are negatively associatedwith clinical response to adoptive immunotherapyof human cancer., ” Blood, vol. 119, no. 24, pp. 5688-96, Jun. 2012.
96. T. Álvaro, M. Lejeune, and M. Salvadó, “Outcome inHodgkin’s lymphoma can be predicted from the presenceof accompanying cytotoxic and regulatory T cells,” Clin. cancer Res., vol. 11, pp. 1467-1473, 2005.
97. A. Tzankov, C. Meier, P. Hirschmann, P. Went, S. Pileri, and S. Dirnhofer, “Correlation of high numbers of intratumoralFOXP3+ regulatory T cells with improved survivalin germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’slymphoma., ” Haematologica, vol. 93, no. 2, pp. 193-200, Feb. 2008.
98. C. Badoual, S. Hans, J. Rodriguez, S. Peyrard, C. Klein, N. E. H. Agueznay, V. Mosseri, O. Laccourreye, P. Bruneval, W. H. Fridman, D. F. Brasnu, and E. Tartour, “Prognosticvalue of tumor-infiltrating CD4+ T-cell subpopulations inhead and neck cancers., ” Clin. cancer Res., vol. 12, no. 2, pp. 465-72, Jan. 2006.
99. P. Salama, M. Phillips, F. Grieu, M. Morris, N. Zeps, D. Joseph, C. Platell, and B. Iacopetta, “Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significancein colorectal cancer., ” J. Clin. Oncol., vol. 27, no. 2, pp. 186-92, Jan. 2009.
100. F. A. Sinicrope, R. L. Rego, S. M. Ansell, K. L. Knutson, and N. R. Foster, “A low intraepithelial effector (CD3+):reulatory (Foxp3+) T-cell ratio predicts adverse outcomeof human colon carcinoma, ” Gastroenterology, vol. 137, no. 4, pp. 1270-1279, 2009.
101. S. A. Quezada, K. S. Peggs, T. R. Simpson, Y. Shen, D. R. Littman, and J. P. Allison, “Limited tumor infiltration byactivated T effector cells restricts the therapeutic activityof regulatory T cell depletion against establishedmelanoma., ” J. Exp. Med., vol. 205, no. 9, pp. 2125-38, Sep. 2008.
102. N. Chaput, R. Conforti, S. Viaud, A Spatz, and L. Zitvogel, “The Janus face of dendritic cells in cancer., ” Oncogene, vol. 27, no. 45, pp. 5920-31, Oct. 2008.
103. A. Hagymasi and A. Slaiby, “Steady state dendritic cellspresent parenchymal self-antigen and contribute to, butare not essential for, tolerization of naive and Th1 effectorCD4 cells,” J. Immunol., vol. 179, no. 3, pp. 1524-1531, 2007.
104. M. R. Shurin, H. Naiditch, H. Zhong, and G. V. Shurin, “Regulatory dendritic cells: New targets for cancer immunotherapy,” Cancer Biol. Ther., vol. 11, no. 11, pp. 988-992, Jun. 2011.
105. A. Enk, H. Jonuleit, J. Saloga, and J. Knop, “Dendriticcells as mediators of tumor-induced tolerance in metastaticmelanoma., ” Int. J. Cancer, vol. 73, no. 3, pp. 309-16, Nov. 1997.
106. D. I. Gabrilovich, J. Corak, I. F. Ciernik, D. Kavanaugh, and D. P. Carbone, “Decreased antigen presentation bydendritic cells in patients with breast cancer., ” Clin. Cancer Res., vol. 3, no. 3, pp. 483-90, Mar. 1997.
107. S. K. Watkins, Z. Zhu, E. Riboldi, K. A. Shafer-weaver, K. E. R. Stagliano, M. M. Sklavos, S. Ambs, H. Yagita, and A. A. Hurwitz, “FOXO3 programs tumor-associated DCs tobecome tolerogenic in human and murine prostate cancer,” J. Clin. Invest., vol. 121, no. 4, pp. 1361-72, 2011.
108. M. Aalamian, G. Pirtskhalaishvili, a Nunez, C. Esche, G. VShurin, E. Huland, H. Huland, and M. R. Shurin, “Humanprostate cancer regulates generation and maturation ofmonocyte-derived dendritic cells.,” Prostate, vol. 46, no. 1, pp. 68-75, Jan. 2001.
109. I. Treilleux and J. Blay, “Dendritic cell infiltration andprognosis of early stage breast cancer, ” Clin. cancerRes., vol. 10, pp. 7466-7474, 2004.
110. W. Zou, V. Machelon, A CoulombL’Hermin, J. Borvak, F. Nome, T. Isaeva, S. Wei, R. Krzysiek, I. Durand-Gasselin, A Gordon, T. Pustilnik, D. T. Curiel, P. Galanaud, F. Capron, D. Emilie, and T. J. Curiel, “Stromal-derived factor-1 in human tumors recruits and alters the functionof plasmacytoid precursor dendritic cells., ” Nat. Med., vol. 7, no. 12, pp. 1339-46, Dec. 2001.
111. S. Wei, I. Kryczek, L. Zou, B. Daniel, P. Cheng, P. Mottram, T. Curiel, A. Lange, and W. Zou, “Plasmacytoiddendritic cells induce CD8+ regulatory T cells in humanovarian carcinoma.,” Cancer Res., vol. 65, no. 12, pp. 5020-6, Jun. 2005.
112. D. Munn, M. Sharma, and D. Hou, “Expression of indoleamine2, 3-dioxygenase by plasmacytoid dendriticcells in tumor-draining lymph nodes, ” J. Clin. Investig., vol. 114, no. 2, 2004.
113. D. H. Munn, M. D. Sharma, J. R. Lee, K. G. Jhaver, T. S. Johnson, D. B. Keskin, B. Marshall, P. Chandler, S. J. Antonia, R. Burgess, C. L. Slingluff, and A. L. Mellor, “Potentialregulatory function of human dendritic cells expressingindoleamine 2, 3-dioxygenase., ” Science, vol. 297, no. 5588, pp. 1867-70, Sep. 2002.
114. L. Norian, P. Rodriguez, and L. O’Mara, “Tumorinfiltratingregulatory dendritic cells inhibit CD8+ T cellfunction via L-arginine metabolism, ” Cancer Res., vol. 69, no. 7, pp. 3086-3094, 2009.
115. V. Bronte, “Tolerogenic pDCs: spotlight on Foxo3, ” J. Clin. Invest., vol. 15, no. 1, pp. 11-14, 2011.
116. S. Watkins and A. Hurwitz, “FOXO3: a master switch forregulating tolerance and immunity in dendritic cells,” Oncoimmunology, vol. 1, no. 2, pp. 252-254, 2012.
117. A. Dejean, D. Beisner, I. Ch’en, Y. Kerdiles, A. Babour, K. Arden, D. Castrillon, R. DePinho, and S. Hedrick, “Foxo3controls the magnitude of T cell immune responses bymodulating dendritic cell function, ” Nat. Immunol., vol. 10, no. 5, pp. 504-513, 2009.
118. J. C. Lee, M. Espéli, C. Anderson, M. Linterman, J. M. Pocock, N. J. Williams, R. Roberts, S. Viatte, B. Fu, N. Peshu, T. T. Hien, N. H. Phu, E. Wesley, C. Edwards, T. Ahmad, J. C. Mansfield, R. Gearry, S. Dunstan, T. N. Williams, A. Barton, C. G. Vinuesa, M. Parkes, P. Lyons, and K. G. C. Smith, “Human SNP Links Differential Outcomesin Inflammatory and Infectious Disease to aFOXO3-Regulated Pathway.,” Cell, pp. 57-69, Sep. 2013.
119. A. Brunet, A. Bonni, M. Zigmond, M. Lin, and P. Juo, “Aktpromotes cell survival by phosphorylating and inhibitinga Forkhead transcription factor,” Cell, vol. 96, pp. 857-868, 1999.
120. W. Ouyang and M. Li, “Foxo: in command of T lymphocytehomeostasis and tolerance, ” Trends Immunol., vol. 32, no. 1, pp. 26-33, 2011.
121. G. J. P. L. Kops, T. B. Dansen, P. E. Polderman, and J. L. Bos, “Forkhead transcription factor FOXO3a protectsquiescent cells from oxidative stress,” vol. 419, no. September, pp. 316-321, 2002.
122. B. J. Willcox, T. Donlon, Q. He, R. Chen, J. S. Grove, K. Yano, K. H. Masaki, D. C. Willcox, B. Rodriguez, and J. D. Curb, “FOXO3A genotype is strongly associated withhuman longevity., ” Proc. Natl. Acad. Sci. U. S. A., vol. 105, no. 37, pp. 13987-92, Sep. 2008.
123. K. Maiese, J. Hou, Z. Z. Chong, and Y. C. Shang, “Developingtherapeutic inroads with FoxO proteins,” Oxid. Med. Cell. Longev., vol. 2, no. August, pp. 119-129, 2009.
124. J. Paik, R. Kollipara, G. Chu, H. Ji, and Y. Xiao, “FoxOs arelineage-restricted redundant tumor suppressors andregulate endothelial cell homeostasis, ” Cell, vol. 128, no. 2, pp. 309-323, 2007.
125. C. Yu, Z. Zhang, W. Liao, X. Zhao, L. Liu, Y. Wu, Z. Liu, Y. Li, Y. Zhong, K. Chen, J. Li, F. Zhou, and L. Song, “Thetumor-suppressor gene Nkx2 8 suppresses bladder cancerproliferation through upregulation of FOXO3a andinhibition of the MEK/ERK signaling pathway., ” Carcinogenesis, vol. 33, no. 3, pp. 678-86, Mar. 2012.
126. M. C. -T. Hu, D.-F. Lee, W. Xia, L. S. Golfman, F. Ou-Yang, J. -Y. Yang, Y. Zou, S. Bao, N. Hanada, H. Saso, R. Kobayashi, and M.-C. Hung, “IkappaB kinase promotes tumorigenesisthrough inhibition of forkhead FOXO3a.,” Cell, vol. 117, no. 2, pp. 225-37, Apr. 2004.
127. N. Nakamura, S. Ramaswamy, F. Vazquez, S. Signoretti, M. Loda, and W. R. Sellers, “Forkhead Transcription FactorsAre Critical Effectors of Cell Death and Cell Cycle ArrestDownstream of PTEN,” Mol. Cell. Biol., vol. 20, no. 23, pp. 8969-8982, 2000.
128. Y. Harada, Y. Harada, C. Elly, G. Ying, J. -H. Paik, R. aDePinho, and Y. -C. Liu, “Transcription factors Foxo3aand Foxo1 couple the E3 ligase Cbl-b to the induction ofFoxp3 expression in induced regulatory T cells., ” J. Exp. Med., vol. 207, no. 7, pp. 1381-91, Jul. 2010.
129. Y. Kerdiles, E. Stone, and D. Beisner, “Foxo transcriptionfactors control regulatory T cell development and function,” Immunity, vol. 33, no. 6, pp. 890-904, 2010.
130. W. Ouyang, O. Beckett, Q. Ma, J. Paik, R. DePinho, M. O. Li, “Foxo proteins cooperatively control the differentiationof Foxp3+ regulatory T cells., ” Nat. Immunol., vol. 11, no. 7, pp. 618-27, Jul. 2010.
131. M. Lappas, R. Lim, C. Riley, R. Menon, and M. Permezel, “Expression and localisation of FoxO3 and FoxO4 in humanplacenta and fetal membranes., ” Placenta, vol. 31, no. 12, pp. 1043-50, Dec. 2010.
132. L. Snoeks, C. R. Weber, K. Wasland, J. R. Turner, W. Qi, and S. D. Savkovic, “Tumor suppressor FOXO3 participatesin the regulation of intestinal inflammation, ” Lab. Investig., vol. 89, no. 9, pp. 1053-1062, 2009.
133. E. Vacchelli and L. Galluzzi, “Trial Watch: Immunostimulatorycytokines, ” Oncoimmunology, vol. 1, no. 4, pp. 493-506, 2012.
134. M. Ahmadzadeh and S. Rosenberg, “IL-2 administrationincreases CD4+ CD25(hi) Foxp3+ regulatory T cellsin cancer patients., ” Blood, vol. 107, no. 6, pp. 2409-14, Mar. 2006.
135. M. E. Dudley, J. R. Wunderlich, J. C. Yang, R. M. Sherry, S. L. Topalian, N. P. Restifo, R. E. Royal, U. Kammula, D. E. White, S. Mavroukakis, L. J. Rogers, G. J. Gracia, S. aJones, D. P. Mangiameli, M. M. Pelletier, J. Gea-Banacloche, M. R. Robinson, D. M. Berman, A. C. Filie, A. Abati, and S. A. Rosenberg, “Adoptive cell transfer therapyfollowing non-myeloablative but lymphodepletingchemotherapy for the treatment of patients with refractorymetastatic melanoma., ” J. Clin. Oncol., vol. 23, no. 10, pp. 2346-57, Apr. 2005.
136. S. A. Rosenberg, “Cell transfer immunotherapy for metastaticsolid cancer--what clinicians need to know.,” Nat. Rev. Clin. Oncol., vol. 8, no. 10, pp. 577-85, Oct. 2011.
137. K. Palucka and J. Banchereau, “Dendritic-cell-basedtherapeutic cancer vaccines., ” Immunity, vol. 39, no. 1, pp. 38-48, Jul. 2013.
138. P. Kantoff and C. Higano, “Sipuleucel-T immunotherapyfor castration-resistant prostate cancer, ” N. Engl. J. Med., vol. 363, no. 5, pp. 411-422, 2010.
139. M. Kalos, B. Levine, and D. Porter, “T cells with chimericantigen receptors have potent antitumor effects andcan establish memory in patients with advanced leukemia,” Sci. Transl. Med., vol. 3, no. 95, 2011.
140. M. E. Dudley, J. C. Yang, R. Sherry, M. S. Hughes, R. Royal, U. Kammula, P. F. Robbins, J. Huang, D. E. Citrin, S. F. Leitman, J. Wunderlich, N. P. Restifo, A. Thomasian, S. G. Downey, F. O. Smith, J. Klapper, K. Morton, C. Laurencot, D. E. White, and S. Rosenberg, “Adoptive celltherapy for patients with metastatic melanoma: evaluationof intensive myeloablative chemoradiation preparativeregimens.,” J. Clin. Oncol., vol. 26, no. 32, pp. 5233-9, Nov. 2008.
141. S. Rosenberg, J. Yang, and R. Sherry, “Durable completeresponses in heavily pretreated patients with metastaticmelanoma using T-cell transfer immunotherapy, ” Clin. cancer Res., vol. 17, no. 13, pp. 4550-4557, 2011.
142. M. E. Dudley, C. Gross, R. P. T. Somerville, Y. Hong, N. P. Schaub, S. F. Rosati, D. E. White, D. Nathan, N. P. Restifo, S. M. Steinberg, J. R. Wunderlich, U. S. Kammula, R. M. Sherry, J. C. Yang, G. Q. Phan, M. S. Hughes, C. M. Laurencot, and S. Rosenberg, “Randomized selectiondesign trial evaluating CD8+-enriched versus unselectedtumor-infiltrating lymphocytes for adoptive cell therapyfor patients with melanoma., ” J. Clin. Oncol., vol. 31, no. 17, pp. 2152-9, Jun. 2013.
143. M. Donia, M. Hansen, S. L. Sendrup, T. Z. Iversen, E. Ellebæk, M. H. Andersen, P. T. Straten, and I. M. Svane, “Methods to improve adoptive T-cell therapy for melanoma:IFN-γ enhances anticancer responses of cellproducts for infusion., ” J. Invest. Dermatol., vol. 133, no. 2, pp. 545-52, Feb. 2013.
144. N. N. Hunder, H. Wallen, J. Cao, D. W. Hendricks, J. Z. Reilly, R. Rodmyre, A. Jungbluth, S. Gnjatic, J. Thompson, and C. Yee, “Treatment of metastatic melanomawith autologous CD4+ T cells against NY-ESO-1.,” N. Engl. J. Med., vol. 358, no. 25, pp. 2698-703, Jun. 2008.
145. L. Galluzzi, E. Vacchelli, A. Eggermont, W. H. Fridman, J. Galon, C. Sautès-Fridman, E. Tartour, L. Zitvogel, and G. Kroemer, “Trial Watch: Adoptive cell transfer immunotherapy.,” Oncoimmunology, vol. 1, no. 3, pp. 306-315, May 2012.
146. L. Galluzzi, E. Vacchelli, W. H. Fridman, J. Galon, C. Sautès-fridman, and E. Tartour, “Monoclonal antibodiesin cancer therapy Trial watch, ” Oncoimmunology, vol. 1, no. 1, pp. 28-37, 2012.
147. S. Hodi, S. O’Day, D. McDermott, R. Weber, J. A. Sosman, J. B. Haanen, R. Gonzalez, C. Robert, D. Ph, D. Schadendorf, J. C. Hassel, W. Akerley, A. J. M. Van DenEertwegh, J. Lutzky, P. Lorigan, J. M. Vaubel, G. P. Linette, D. Hogg, C. H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J. I. Clark, J. D. Wolchok, J. S. Weber, J. Tian, M. J. Yellin, G. M. Nichol, B. Ch, A. Hoos, and W. J. Urba, “Improved Survival with Ipilimumap in Patientswith Metastatic Melanoma,” N. Engl. J. Med., vol. 363, no. 8, pp. 711-723, 2010.
148. D. B. Page, M. Postow, M. K. Callahan, and J. D. Wolchok, “Checkpoint Modulation in Melanoma: An Updateon Ipilimumab and Future Directions.,” Curr. Oncol. Rep., Aug. 2013.
149. S. Topalian, S. Hodi, J. Brahmer, D. C. Smith, D. F. Mcdermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J. Antonia, D. Ph, L. Horn, C. G. Drake, D. M. Pardoll, L. Chen, W. H. Sharfman, R. A. Anders, J. M. Taube, T. L. Mcmiller, H. Xu, A. J. Korman, M. Jure-kunkel, S. Agrawal, and M. Sznol, “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer, ” N. Engl. J. Med., vol. 366, no. 26, pp. 2443-2454, 2012.
150. J. R. Brahmer, S. S. Tykodi, L. Q. M. Chow, W. -J. Hwu, S. L. Topalian, P. Hwu, C. G. Drake, L. H. Camacho, J. Kauh, K. Odunsi, H. C. Pitot, O. Hamid, S. Bhatia, R. Martins, K. Eaton, S. Chen, T. M. Salay, S. Alaparthy, J. F. Grosso, A. J. Korman, S. M. Parker, S. Agrawal, S. M. Goldberg, D. M. Pardoll, A. Gupta, and J. M. Wigginton, “Safety andactivity of anti-PD-L1 antibody in patients with advancedcancer.,” N. Engl. J. Med., vol. 366, no. 26, pp. 2455-65, Jun. 2012.
151. K. S. Peggs and S. Quezada, “PD-1 blockade: promotingendogenous anti-tumor immunity.,” Expert Rev. AnticancerTher., vol. 12, no. 10, pp. 1279-82, Oct. 2012.
152. D. O’Mahony and J. Janik, “Comment on ‘Analysis of theCellular Mechanism of Antitumor Responses and Autoimmunityin Patients Treated with CTLA-4 Blockade’, ” J. Immunol., vol. 176, p. 5136, 2006.
153. A. J. Rech, R. Mick, S. Martin, A. Recio, N. Aqui, D. J. Powell, T. Colligon, J. Trosko, L. I. Leinbach, C. H. Pletcher, C. K. Tweed, A. DeMichele, K. R. Fox, S. M. Domchek, J. L. Riley, and R. H. Vonderheide, “CD25blockade depletes and selectively reprograms regulatoryT cells in concert with immunotherapy in cancer patients.,” Sci. Transl. Med., vol. 4, no. 134, p. 134-62, May 2012.
154. L. Galluzzi, L. Senovilla, L. Zitvogel, and G. Kroemer, “Thesecret ally: immunostimulation by anticancer drugs., ”Nat. Rev. Drug Discov., vol. 11, no. 3, pp. 215-33, Mar. 2012.
155. G. Chen and L. Emens, “Chemoimmunotherapy: reengineeringtumor immunity., ” Cancer Immunol. Immunother., vol. 62, no. 2, pp. 203-16, Feb. 2013.
156. L. Zitvogel, O. Kepp, L. Senovilla, L. Menger, N. Chaput, and G. Kroemer, “Immunogenic tumor cell death for optimalanticancer therapy: the calreticulin exposurepathway., ” Clin. Cancer Res., vol. 16, no. 12, pp. 3100-4, Jun. 2010.
157. S. J. Adair and K. T. Hogan, “Treatment of ovarian cancercell lines with 5-aza-2’-deoxycytidine upregulates theexpression of cancer-testis antigens and class I majorhistocompatibility complex-encoded molecules., ” CancerImmunol. Immunother., vol. 58, no. 4, pp. 589-601, Apr. 2009.
158. E. Fonsatti, H. J. M. Nicolay, L. Sigalotti, L. Calabrò, L. Pezzani, F. Colizzi, M. Altomonte, M. Guidoboni, F. M. Marincola, and M. Maio, “Functional up-regulation ofhuman leukocyte antigen class I antigens expression by5-aza-2’-deoxycytidine in cutaneous melanoma: immunotherapeuticimplications., ” Clin. Cancer Res., vol. 13, no. 11, pp. 3333-8, Jun. 2007.
159. R. Kaneno, G. V Shurin, F. M. Kaneno, H. Naiditch, J. Luo, and M. R. Shurin, “Chemotherapeutic agents in lownoncytotoxic concentrations increase immunogenicityof human colon cancer cells.,” Cell. Oncol., vol. 34, no. 2, pp. 97-106, Apr. 2011.
160. H. Ghebeh, C. Lehe, E. Barhoush, K. Al-Romaih, A. Tulbah, M. Al-Alwan, S. -F. Hendrayani, P. Manogaran, A. Alaiya, T. Al-Tweigeri, A. Aboussekhra, and S. Dermime, “Doxorubicin downregulates cell surface B7-H1 expressionand upregulates its nuclear expression in breastcancer cells: role of B7-H1 as an anti-apoptotic molecule.,” Breast Cancer Res., vol. 12, no. 4, p. R48, Jan. 2010.
161. S. Yang and F. Haluska, “Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme-andFas-mediated pathways, ” J. Immunol., vol. 172, pp. 4599-4608, 2004.
162. M. E. C. Lutsiak, R. T. Semnani, R. De Pascalis, S. V. S. Kashmiri, J. Schlom, and H. Sabzevari, “Inhibition ofCD4(+)25+ T regulatory cell function implicated in enhancedimmune response by low-dose cyclophosphamide., ”Blood, vol. 105, no. 7, pp. 2862-8, Apr. 2005.
163. F. Ghiringhelli, C. Menard, P. E. Puig, S. Ladoire, S. Roux, F. Martin, E. Solary, A. Le Cesne, L. Zitvogel, and B. Chauffert, “Metronomic cyclophosphamide regimen selectivelydepletes CD4+CD25+ regulatory T cells and restoresT and NK effector functions in end stage cancerpatients.,” Cancer Immunol. Immunother., vol. 56, no. 5, pp. 641-8, May 2007.
164. L. Polak and J. Turk, “Reversal of immunological toleranceby cyclophosphamide through inhibition of suppressorcell activity,” Nature, vol. 249, no. June 14, pp. 654-56, 1974.
165. C. Camisaschi, P. Filipazzi, M. Tazzari, C. Casati, V. Beretta, L. Pilla, R. Patuzzo, A. Maurichi, A. Cova, M. Maio, V. Chiarion-Sileni, G. Tragni, M. Santinami, B. Vergani, A. Villa, E. Berti, L. Umansky, P. Beckhove, V. Umansky, G. Parmiani, L. Rivoltini, and C. Castelli, “Effects ofcyclophosphamide and IL-2 on regulatory CD4+ T cellfrequency and function in melanoma patients vaccinatedwith HLA-class I peptides: impact on the antigenspecificT cell response.,” Cancer Immunol. Immunother., vol. 62, no. 5, pp. 897-908, May 2013.
166. L. Zhang, K. Dermawan, M. Jin, R. Liu, H. Zheng, L. Xu, Y. Zhang, Y. Cai, Y. Chu, and S. Xiong, “Differential impairmentof regulatory T cells rather than effector T cells bypaclitaxel-based chemotherapy” Clin. Immunol., vol. 129, no. 2, pp. 219-29, Nov. 2008.
167. M. Beyer, M. Kochanek, K. Darabi, A. Popov, M. Jensen, E. Endl, P. Knolle, R. K. Thomas, M. von Bergwelt-Baildon, S. Debey, M. Hallek, J.L. Schultze, “Reducedfrequencies and suppressive function ofCD4+CD25hi regulatory T cells in patients with chroniclymphocytic leukemia after therapy with fludarabine.,” Blood, vol. 106, no. 6, pp. 2018-25, Sep. 2005.
168. R. Kaneno, G. V Shurin, I. L. Tourkova, and M. R. Shurin, “Chemomodulation of human dendritic cell function byantineoplastic agents in low noncytotoxic concentrations., ”J. Transl. Med., vol. 7, p. 58, Jan. 2009.
169. V. Radojcic, K. B. Bezak, M. Skarica, M. Pletneva, K. Yoshimura, R. D. Schulick, and L. Luznik, “Cyclophosphamideresets dendritic cell homeostasis and enhancesantitumor immunity through effects that extend beyondregulatory T cell elimination., ” Cancer Immunol. Immunother., vol. 59, no. 1, pp. 137-48, Jan. 2010.
170. J. F. M. Jacobs, C. J. Punt, W. J. Lesterhuis, R. P. M. Sutmuller, H. M. -L. H. Brouwer, N. M. Scharenborg, I. S. Klasen, L. B. Hilbrands, C. G. Figdor, I. J. M. de Vries, andG. J. Adema, “Dendritic cell vaccination in combinationwith anti-CD25 monoclonal antibody treatment: a phaseI/II study in metastatic melanoma patients., ” Clin. CancerRes., vol. 16, no. 20, pp. 5067-78, Oct. 2010.
171. J. Dannull, Z. Su, and D. Rizzieri, “Enhancement of vaccine-mediated antitumor immunity in cancer patientsafter depletion of regulatory T cells, ” J. Clin. Investig., vol. 115, no. 12, pp. 3623-3633, 2005.
172. M. A. Rasku, A. L. Clem, S. Telang, B. Taft, K. Gettings, H. Gragg, D. Cramer, S. C. Lear, K. M. McMasters, D. M. Miller, and J. Chesney, “Transient T cell depletion causes regression of melanoma metastases., ” J. Transl. Med., vol. 6, p. 12, Jan. 2008.
173. P. Attia, A. Maker, and L. Haworth, “Inability of a fusionprotein of IL-2 and diphtheria toxin (ONTAK) to eliminateregulatory T lymphocytes in patients with melanoma,” J Immunother, vol. 28, no. 6, pp. 582-592, 2005.
174. A. S. Baur, M. B. Lutz, S. Schierer, L. Beltrame, G. Theiner, E. Zinser, C. Ostalecki, G. Heidkamp, I. Haendle, M. Erdmann, M. Wiesinger, W. Leisgang, S. Gross, A. J. Pommer, E. Kämpgen, D. Dudziak, A. Steinkasserer, D. Cavalieri, B. Schuler-Thurner, and G. Schuler, “Denileukindiftitox (ONTAKTM) induces a tolerogenic phenotypein dendritic cells and stimulates survival of restingTreg.,” Blood, Aug. 2013.
175. D. T. Le and E. M. Jaffee, “Regulatory T-cell modulationusing cyclophosphamide in vaccine approaches: a currentperspective.,” Cancer Res., vol. 72, no. 14, pp. 3439-44, Jul. 2012.
176. S. Walter, T. Weinschenk, A. Stenzl, R. Zdrojowy, A. Pluzanska, C. Szczylik, M. Staehler, W. Brugger, P. -Y. Dietrich, R. Mendrzyk, N. Hilf, O. Schoor, J. Fritsche, A. Mahr, D. Maurer, V. Vass, C. Trautwein, P. Lewandrowski, C. Flohr, H. Pohla, J. J. Stanczak, V. Bronte, S. Mandruzzato, T. Biedermann, G. Pawelec, E. Derhovanessian, H. Yamagishi, T. Miki, F. Hongo, N. Takaha, K. Hirakawa, H. Tanaka, S. Stevanovic, J. Frisch, A. Mayer-Mokler, A. Kirner, H. -G. Rammensee, C. Reinhardt, and H. Singh-Jasuja, “Multipeptide immune response tocancer vaccine IMA901 after single-dose cyclophosphamideassociates with longer patient survival., ” Nat. Med., vol. 18, no. 8, Aug. 2012.
177. Y. Ge, C. Domschke, N. Stoiber, S. Schott, J. Heil, J. Rom, M. Blumenstein, J. Thum, C. Sohn, A. Schneeweiss, P. Beckhove, and F. Schuetz, “Metronomic cyclophosphamidetreatment in metastasized breast cancer patients:immunological effects and clinical outcome., ” CancerImmunol. Immunother., vol. 61, no. 3, pp. 353-62, Mar. 2012.
178. E. Ellebaek, L. Engell-Noerregaard, T. Z. Iversen, T. M. Froesig, S. Munir, S. R. Hadrup, M. H. Andersen, and I. M. Svane, “Metastatic melanoma patients treated withdendritic cell vaccination, Interleukin-2 and metronomiccyclophosphamide: results from a phase II trial.,” CancerImmunol. Immunother., vol. 61, no. 10, pp. 1791-804, Oct. 2012.
179. C. Diaz-Montero and M. Salem, “Increased circulatingmyeloid-derived suppressor cells correlate with clinicalcancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy,” Cancer Immunol. Immunother., vol. 58, no. 1, pp. 49-59, 2009.
180. A. Sevko, M. Sade-Feldman, J. Kanterman, T. Michels, C. S. Falk, L. Umansky, M. Ramacher, M. Kato, D. Schadendorf, M. Baniyash, and V. Umansky, “Cyclophosphamidepromotes chronic inflammation-dependent immunosuppressionand prevents antitumor response in melanoma., ”J. Invest. Dermatol., vol. 133, no. 6, pp. 1610-9, Jun. 2013.
181. C. L. Slingluff, G. R. Petroni, K. Chianese-Bullock, M. E. Smolkin, M. I. Ross, N. B. Haas, M. von Mehren, and W. W. Grosh, “Randomized multicenter trial of the effectsof melanoma-associated helper peptides and cyclophosphamideon the immunogenicity of a multipeptidemelanoma vaccine., ” J. Clin. Oncol., vol. 29, no. 21, pp. 2924-32, Jul. 2011.
182. A. Maker, P. Attia, and S. Rosenberg, “Analysis of thecellular mechanism of antitumor responses and autoimmunityin patients treated with CTLA-4 blockade,” J. Immunol., vol. 175, pp. 7746-54, 2005.
183. H. Pere, C. Tanchot, J. Bayry, M. Terme, J. Taieb, C. Badoual, O. Adotevi, N. Merillon, E. Marcheteau, V. R. Quillien, C. Banissi, A. Carpentier, F. Sandoval, M. Nizard, F. Quintin-Colonna, G. Kroemer, W. H. Fridman, L. Zitvogel, S. P. Oudard, and E. Tartour, “Comprehensiveanalysis of current approaches to inhibit regulatoryT cells in cancer.,” Oncoimmunology, vol. 1, no. 3, pp. 326-333, May 2012.
184. O. Adotevi, H. Pere, P. Ravel, N. Haicheur, C. Badoual, N. Merillon, J. Medioni, S. Peyrard, S. Roncelin, V. Verkarre, A. Mejean, W. H. Fridman, S. Oudard, and E. Tartour, “Adecrease of regulatory T cells correlates with overallsurvival after sunitinib-based antiangiogenic therapy inmetastatic renal cancer patients., ” J. Immunother., vol. 33, no. 9, pp. 991-8, 2010.
185. D. Gabrilovich, T. Ishida, and S. Nadaf, “Antibodies tovascular endothelial growth factor enhance the efficacyof cancer immunotherapy by improving endogenousdendritic cell function, ” Clin. cancer Res., vol. 5, pp. 2963-2970, 1999.
186. J. S. Ko, A. H. Zea, B. I. Rini, J. L. Ireland, P. Elson, P. Cohen, A. Golshayan, P. Rayman, L. Wood, J. Garcia, R. Dreicer, R. Bukowski, and J. H. Finke, “Sunitinib mediatesreversal of myeloid-derived suppressor cell accumulationin renal cell carcinoma patients., ” Clin. CancerRes., vol. 15, no. 6, pp. 2148-57, Mar. 2009.
187. V. Balachandran, M. Cavnar, S. Zeng, Z. Bamboat, L. Ocuin, H. Obaid, E. Sorenson, R. Popow, C. Ariyan, F. Rossi, P. Besmer, T. Guo, C. R. Antonescu, and T. Taguchi, “Imatinib potentiates anti-tumor T cell responsesin gastrointestinal stromal tumor through theinhibition of Ido” Nat. Med., vol. 17, no. 9, pp. 1094-1100, 2012.
188. W. Wang, R. Lau, D. Yu, W. Zhu, A. Korman, and J. Weber, “PD1 blockade reverses the suppression of melanomaantigen-specific CTL by CD4+ CD25(Hi) regulatoryT cells.,” Int. Immunol., vol. 21, no. 9, pp. 1065-77, Sep. 2009.
189. C. -Y. Mu, J. -A. Huang, Y. Chen, C. Chen, and X. -G. Zhang, “High expression of PD-L1 in lung cancer may contributeto poor prognosis and tumor cells immune escapethrough suppressing tumor infiltrating dendritic cellsmaturation.,” Med. Oncol., vol. 28, no. 3, pp. 682-8, Sep. 2011.
190. J. A. Brown, D. M. Dorfman, F. -R. Ma, E. L. Sullivan, O. Munoz, C. R. Wood, E. A. Greenfield, and G. J. Freeman, “Blockade of programmed death-1 ligands on dendriticcells enhances T cell activation and cytokine production.,” J. Immunol., vol. 170, no. 3, pp. 1257-66, Feb. 2003.
191. G. Peng, Z. Guo, Y. Kiniwa, K. S. Voo, W. Peng, T. Fu, D. Y. Wang, Y. Li, H. Y. Wang, and R. -F. Wang, “Toll-like receptor8-mediated reversal of CD4+ regulatory T cellfunction.,” Science, vol. 309, no. 5739, pp. 1380-4, Aug. 2005.
192. B. G. Molenkamp, P. M. van Leeuwen, S. Meijer, B. J. R. Sluijter, P. G. J. T. B. Wijnands, A. Baars, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl, “IntradermalCpG-B activates both plasmacytoid and myeloiddendritic cells in the sentinel lymph node of melanomapatients., ” Clin. Cancer Res., vol. 13, no. 10, pp. 2961-9, May 2007.
193. C. Uyttenhove, L. Pilotte, I. Théate, V. Stroobant, D. Colau, N. Parmentier, T. Boon, and B. J. Van den Eynde, “Evidence for a tumoral immune resistance mechanismbased on tryptophan degradation by indoleamine 2, 3-dioxygenase., ” Nat. Med., vol. 9, no. 10, pp. 1269-74, Oct. 2003.
194. E. Dolusic and R. Frederick, “Indoleamine 2, 3-dioxygenase inhibitors : a patent review, ” Expert Opin. ther. patents, vol. 23, no. 10, pp. 1367-1381, 2013.
195. R. B. Sørensen, L. Berge-Hansen, N. Junker, C. A. Hansen, S. R. Hadrup, T. N. M. Schumacher, I. M. Svane, J. C. Becker, P. thor Straten, and M. H. Andersen, “The immunesystem strikes back: cellular immune responsesagainst indoleamine 2, 3-dioxygenase., ” PLoS One, vol. 4, no. 9, p. e6910, Jan. 2009.
196. R. B. Sørensen, S. R. Hadrup, I. M. Svane, M. C. Hjortsø, P. Thor Straten, and M. H. Andersen, “Indoleamine 2, 3-dioxygenase specific, cytotoxic T cells as immune regulators.,” Blood, vol. 117, no. 7, pp. 2200-10, Feb. 2011.
197. S. Munir, S. K. Larsen, T. Z. Iversen, M. Donia, T. W. Klausen, I. M. Svane, P. T. Straten, and M. H. Andersen, “Natural CD4+ T-cell responses against indoleamine 2, 3-dioxygenase., ” PLoS One, vol. 7, no. 4, p. e34568, Jan. 2012.
198. T. Iversen, L. Engell-Nørregård, E. Ellebæk, R. Andersen, S. Larsen, J. Bjørn, H. Balbacher, C. Zeyher, C. Gouttefangeas, B. Thomsen, B. Holm, A. Mellemgård, P. thor Straten, M. Andersen, and I. Svane, “Lack of toxicityduring long-lasting disease stabilization in metastaticlung cancer patients vaccinated with an HLA-A2-restricted epitope derived from indoleamine 2, 3-dioxygenase, ” Submitt. to Clin. cancer Res.
199. S. Munir, G. H. Andersen, Ö. Met, M. Donia, T. M. Frøsig, S. K. Larsen, T. W. Klausen, I. M. Svane, and M. H. Andersen, “HLA-restricted CTL that are specific for theimmune checkpoint ligand PD-L1 occur with high frequencyin cancer patients., ” Cancer Res., vol. 73, no. 6, pp. 1764-76, Mar. 2013.
200. S. Munir, G. H. Andersen, Woetmann, N. Odum, J. C. Becker, and M. H. Andersen, “Cutaneous T cell lymphomacells are targets for immune checkpoint ligandPD-L1-specific, cytotoxic T cells., ” Leukemia, vol. 1, pp. 1-2, Apr. 2013.
201. S. Munir, G. H. Andersen, I. M. Svane, and M. H. Andersen, “The immune checkpoint regulator PD-L1 is a specifictarget for naturally occurring CD4(+) T cells., ” Oncoimmunology, vol. 2, no. 4, p. e23991, Apr. 2013.
202. S. Nair, D. Boczkowski, M. Fassnacht, D. Pisetsky, and E. Gilboa, “Vaccination against the forkhead family transcriptionfactor Foxp3 enhances tumor immunity., ”Cancer Res., vol. 67, no. 1, pp. 371-80, Jan. 2007.
203. S. Hori, T. Nomura, and S. Sakaguchi,Control of regulatoryT cell development by the transcription factorFoxp3., Science (80-.)., vol. 299, no. 5609, pp. 1057-61, Feb. 2003.
204. M. Mandal, K. M. Crusio, F. Meng, S. Liu, M. Kinsella, M. R. Clark, O. Takeuchi, and I. Aifantis, “Regulation of lymphocyteprogenitor survival by the proapoptotic activitiesof Bim and Bid., ” Proc. Natl. Acad. Sci. U. S. A., vol. 105, no. 52, pp. 20840-5, Dec. 2008.
205. C. Feig and M. E. Peter, “How apoptosis got the immunesystem in shape., ” Eur. J. Immunol., vol. 37 Suppl 1, pp. S61-70, Nov. 2007.
206. T. van Es, G. H. M. van Puijvelde, C. Foks, K. L. L. Habets, I. Bot, E. Gilboa, T. J. C. Van Berkel, and J. Kuiper, “Vaccination against Foxp3(+) regulatory T cells aggravatesatherosclerosis., ” Atherosclerosis, vol. 209, no. 1, pp. 74-80, Mar. 2010.
207. L. M. Ebert, S. E. Macraild, D. Zanker, I. D. Davis, J. Cebon, and W. Chen, “A Cancer Vaccine Induces Expansionof NY-ESO-1-Specific Regulatory T Cells in Patients withAdvanced Melanoma., ” PLoS One, vol. 7, no. 10, p. e48424, Jan. 2012.