Targeting cytochrome P450 CYP1B1 with a therapeutic cancer vaccine

Expert Review of Vaccines

Volumn 7, Issue 7, 2008, Pages 995-1003

  Luby, Thomas M ^a  

^a MGI Pharma Biologics   (United States)

Author keywords

Cytochrome P450 1B1; Immunotherapy; Plasmid DNA; Poly(lactide co glycolide); Tumor associated antigen; ZYC300

Indexed keywords

CANCER VACCINE; CYCLOPHOSPHAMIDE; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; CYTOCHROME P450 1B1; DOCETAXEL; FLUTAMIDE; MESSENGER RNA; MITOXANTRONE; MONOCLONAL ANTIBODY; MUCIN 1; PACLITAXEL; PLASMID DNA; POLYGLACTIN; SYNTHETIC PEPTIDE; TUMOR ANTIGEN; UNCLASSIFIED DRUG; ZYC 300;

ACTIVE IMMUNIZATION; ANTIGEN EXPRESSION; ANTIGEN PRESENTATION; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CHRONIC INFLAMMATION; CLINICAL TRIAL; COMPETITIVE INHIBITION; CYP1B1 GENE; DRUG EFFICACY; GENE; HUMAN; HUMAN CELL; INJECTION SITE REACTION; PASSIVE IMMUNIZATION; PRIORITY JOURNAL; PROMOTER REGION; REGULATORY T LYMPHOCYTE; REVIEW; STEROID METABOLISM;

ARYL HYDROCARBON HYDROXYLASES; CANCER VACCINES; HUMANS;

EID: 51349133648     PISSN: 14760584     EISSN: 17448395     Source Type: Journal    
DOI: 10.1586/14760584.7.7.995     Document Type: Review

References (109)

1. Farrell A. Hide and seek. Nature Milestones Cancer 1, DOI:10.1038/nrc1845 (2006) (Epub ahead of print).
2. Bui JD, Schreiber RD. Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr. Opin. Immunol. 19(2), 203-208 (2007).
3. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329-360 (2004).
4. Parton M, Gore M, Eisen T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer. J. Clin. Oncol. 24(35), 5584-5592 (2006).
5. Sharma P, Old LJ, Allison JP. Immunotherapeutic strategies for high-risk bladder cancer. Semin. Oncol. 34(2), 165-172 (2007).
6. Maloney DG. Immunotherapy for non-Hodgkin's lymphoma: monoclonal antibodies and vaccines. J. Clin. Oncol. 23(26), 6421-6428 (2005).
7. Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene 26(25), 3637-3643 (2007).
8. Graziano DF, Finn OJ. Tumor antigens and tumor antigen discovery. Cancer Treat. Res. 123, 89-111 (2005).
9. Wolchok JD, Yuan J, Houghton AN et al. Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol. Ther. 15(11), 2044-2050 (2007).
10. Acres B, Limacher JM. MUC1 as a target antigen for cancer immunotherapy. Expert Rev. Vaccines 4(4), 493-502 (2005).
11. Huang EH, Kaufman HL. CEA-based vaccines. Expert Rev. Vaccines 1(1), 49-63 (2002).
12. Sutter TR, Tang YM, Hayes CL et al. Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2. J. Biol. Chem. 269(18), 13092-13099 (1994). • Identification of CYP1B1 as dioxin-inducible member of the CYP1 family.
13. Shen Z, Wells RL, Elkind MM. Enhanced cytochrome P450 (Cyp1b1) expression, aryl hydrocarbon hydroxylase activity, cytotoxicity, and transformation of C3H 10T1/2 cells by dimethylbenz(a)anthracene in conditioned medium. Cancer Res. 54(15), 4052-4056 (1994).
14. Sissung TM, Price DK, Sparreboom A, Figg WD. Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention. Mol. Cancer Res. 4(3), 135-150 (2006).
15. Alexander DL, Eltom SE, Jefcoate CR. Ah receptor regulation of CYP1B1 expression in primary mouse embryo-derived cells. Cancer Res. 57(20), 4498-4506 (1997).
16. Savas U, Jefcoate CR. Dual regulation of cytochrome P450EF expression via the aryl hydrocarbon receptor and protein stabilization in C3H/10T1/2 cells. Mol. Pharmacol. 45(6), 1153-1159 (1994).
17. Murray GI, Taylor MC, McFadyen MC et al. Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. 57(14), 3026-3031 (1997). • First demonstration of the overexpression of CYP1B1 on tumors and lack of normal tissue staining.
18. McFadyen MC, Breeman S, Payne S et al. Immunohistochemical localization of cytochrome P450 CYP1B1 in breast cancer with monoclonal antibodies specific for CYP1B1. J. Histochem. Cytochem. 47(11), 1457-1464 (1999).
19. Gibson P, Gill JH, Khan PA et al. Cytochrome P450 1B1 (CYP1B1) is overexpressed in human colon adenocarcinomas relative to normal colon: implications for drug development. Mol. Cancer Ther. 2(6), 527-534 (2003).
20. Kumarakulasingham M, Rooney PH, Dundas SR et al. Cytochrome P450 profile of colorectal cancer: identification of markers of prognosis. Clin. Cancer Res. 11(10), 3758-3765 (2005).
21. Downie D, McFadyen MC, Rooney PH et al. Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers. Clin. Cancer Res. 11(20), 7369-7375 (2005).
22. McFadyen MC, Cruickshank ME, Miller ID et al. Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer. Br. J. Cancer 85(2), 242-246 (2001).
23. Barnett JA, Urbauer DL, Murray GI, Fuller GN, Heimberger AB. Cytochrome P450 1B1 expression in glial cell tumors: an immunotherapeutic target. Clin. Cancer Res. 13(12), 3559-3567 (2007).
24. Carnell DM, Smith RE, Daley FM et al. Target validation of cytochrome P450 CYP1B1 in prostate carcinoma with protein expression in associated hyperplastic and premalignant tissue. Int. J. Radiat. Oncol. Biol. Phys. 58(2), 500-509 (2004).
25. McFadyen MC, Melvin WT, Murray GI. Cytochrome P450 CYP1B1 activity in renal cell carcinoma. Br. J. Cancer 91(5), 966-971 (2004).
26. McFadyen MC, Murray GI. Cytochrome P450 1B1: a novel anticancer therapeutic target. Future Oncol. 1(2), 259-263 (2005).
27. Maecker B, Sherr DH, Vonderheide RH et al. The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood 102(9), 3287-3294 (2003). • Report showing that a CYP1B1 peptide is naturally processed and presented on tumor cells and that T cells specific for this peptide could be found in cancer patients.
28. Kim JH, Sherman ME, Curriero FC et al. Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers. Toxicol. Appl. Pharmacol. 199(3), 210-219 (2004).
29. Spivack SD, Hurteau GJ, Reilly AA et al. CYP1B1 expression in human lung. Drug Metab. Dispos. 29(6), 916-922 (2001).
30. Dassi C, Signorini S, Gerthoux P, Cazzaniga M, Brambilla P. Cytochrome P450 1B1 mRNA measured in blood mononuclear cells by quantitative reverse transcription-PCR. Clin. Chem. 44(12), 2416-2421 (1998).
31. Lin P, Hu SW, Chang TH. Correlation between gene expression of aryl hydrocarbon receptor (AhR), hydrocarbon receptor nuclear translocator (Arnt), cytochromes P4501A1 (CYP1A1) and 1B1 (CYP1B1), and inducibility of CYP1A1 and CYP1B1 in human lymphocytes. Toxicol. Sci. 71(1), 20-26 (2003).
32. Port JL, Yamaguchi K, Du B et al. Tobacco smoke induces CYP1B1 in the aerodigestive tract. Carcinogenesis 25(11), 2275-2281 (2004).
33. Willey JC, Coy EL, Frampton MW et al. Quantitative RT-PCR measurement of cytochromes p450 1A1, 1B1, and 2B7, microsomal epoxide hydrolase, and NADPH oxidoreductase expression in lung cells of smokers and nonsmokers. Am. J. Respir. Cell. Mol. Biol. 17(1), 114-124 (1997).
34. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51-81 (2006).
35. Li D, Wang M, Dhingra K, Hittelman WN. Aromatic DNA adducts in adjacent tissues of breast cancer patients: clues to breast cancer etiology. Cancer Res. 56(2), 287-293 (1996).
36. Ross J, Nelson G, Kligerman A et al. Formation and persistence of novel benzo(a)pyrene adducts in rat lung, liver, and peripheral blood lymphocyte DNA. Cancer Res. 50(16), 5088-5094 (1990).
37. van Schooten FJ, Hillebrand MJ, Scherer E, den Engelse L, Kriek E. Immunocytochemical visualization of DNA adducts in mouse tissues and human white blood cells following treatment with benzo[a]pyrene or its diol epoxide. A quantitative approach. Carcinogenesis 12(3), 427-433 (1991).
38. Zenzes MT, Puy LA, Bielecki R. Immunodetection of benzo[a]pyrene adducts in ovarian cells of women exposed to cigarette smoke. Mol. Hum. Reprod. 4(2), 159-165 (1998).
39. Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA. Environmental and chemical carcinogenesis. Semin. Cancer Biol. 14(6), 473-486 (2004).
40. Baird WM, Hooven LA, Mahadevan B. Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ. Mol. Mutagen. 45(2-3), 106-114 (2005).
41. Mahadevan B, Luch A, Atkin J et al. Inhibition of human cytochrome P450 1b1 further clarifies its role in the activation of dibenzo[a,l]pyrene in cells in culture. J. Biochem. Mol. Toxicol. 21(3), 101-109 (2007).
42. Bowes RC, 3rd, Parrish AR, Steinberg MA et al. Atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level. Evidence for CYP1A1 and CYP1B1 expression and their involvement in benzo[a]pyrene metabolism. Biochem. Pharmacol. 52(4), 587-595 (1996).
43. Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol. Appl. Pharmacol. 206(1), 73-93 (2005).
44. Crespi CL, Penman BW, Steimel DT et al. Development of a human lymphoblastoid cell line constitutively expressing human CYP1B1 cDNA: substrate specificity with model substrates and promutagens. Mutagenesis 12(2), 83-89 (1997).
45. Pottenger LH, Christou M, Jefcoate CR. Purification and immunological characterization of a novel cytochrome P450 from C3H/10T1/2 cells. Arch. Biochem. Biophys. 286(2), 488-497 (1991).
46. Pottenger LH, Jefcoate CR. Characterization of a novel cytochrome P450 from the transformable cell line, C3H/10T1/2. Carcinogenesis 11(2), 321-327 (1990).
47. Hankinson O. The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol. 35, 307-340 (1995).
48. Hushka LJ, Williams JS, Greenlee WF. Characterization of 2,3,7,8-tetrachlorodibenzofuran-dependent suppression and AH receptor pathway gene expression in the developing mouse mammary gland. Toxicol. Appl. Pharmacol. 152(1), 200-210 (1998).
49. Rowlands JC, Gustafsson JA. Aryl hydrocarbon receptor-mediated signal transduction. Crit. Rev. Toxicol. 27(2), 109-134 (1997).
50. Safe S, Krishnan V. Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. Arch. Toxicol. Suppl. 17, 99-115 (1995).
51. Piscaglia F, Knittel T, Kobold D et al. Cellular localization of hepatic cytochrome 1B1 expression and its regulation by aromatic hydrocarbons and inflammatory cytokines. Biochem. Pharmacol. 58(1), 157-165 (1999).
52. Umannova L, Machala M, Topinka J et al. Tumor necrosis factor-a potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression. Mutat. Res. 640(1-2), 162-169 (2008).
53. Umannova L, Zatloukalova J, Machala M et al. Tumor necrosis factor-a modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells. Toxicol. Sci. 99(1), 79-89 (2007).
54. Abdel-Razzak Z, Corcos L, Fautrel A, Campion JP, Guillouzo A. Transforming growth factor-β 1 down-regulates basal and polycyclic aromatic hydrocarbon-induced cytochromes P-450 1A1 and 1A2 in adult human hepatocytes in primary culture. Mol. Pharmacol. 46(6), 1100-1110 (1994).
55. Ke S, Rabson AB, Germino JF, Gallo MA, Tian Y. Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-a and lipopolysaccharide. J. Biol. Chem. 276(43), 39638-39644 (2001).
56. Wen X, Walle T. Cytochrome P450 1B1, a novel chemopreventive target for benzo[a]pyrene-initiated human esophageal cancer. Cancer Lett. 246(1-2), 109-114 (2007).
57. Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274(5286), 430-432 (1996).
58. Pfeifer GP, Denissenko MF, Olivier M et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21(48), 7435-7451 (2002).
59. Trombino AF, Near RI, Matulka RA et al. Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis. Breast Cancer Res. Treat. 63(2), 117-131 (2000).
60. Andersson P, McGuire J, Rubio C et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA 99(15), 9990-9995 (2002).
61. Spink DC, Hayes CL, Young NR et al. The effects of 2,3,7,8-tetrachlorodibenzo-pdioxin on estrogen metabolism in MCF-7 breast cancer cells: evidence for induction of a novel 17 β-estradiol 4-hydroxylase. J. Steroid Biochem. Mol. Biol. 51(5-6), 251-258 (1994).
62. Liehr JG. Is estradiol a genotoxic mutagenic carcinogen? Endocr. Rev. 21(1), 40-54 (2000).
63. Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF. Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res. 67(2), 812-817 (2007).
64. Buters JT, Sakai S, Richter T et al. Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a] anthracene-induced lymphomas. Proc. Natl Acad. Sci. USA 96(5), 1977-1982 (1999). • Report showing that mice lacking CYP1B1 did not form tumors upon exposure to a known carcinogen, formally establishing a link between expression of CYP1B1 and tumorigenesis.
65. Rochat B, Morsman JM, Murray GI, Figg WD, McLeod HL. Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? J. Pharmacol. Exp. Ther. 296(2), 537-541 (2001).
66. McFadyen MC, McLeod HL, Jackson FC et al. Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. Biochem. Pharmacol. 62(2), 207-212 (2001).
67. Bournique B, Lemarie A. Docetaxel (taxotere) is not metabolized by recombinant human CYP1B1 in vitro, but acts as an effector of this isozyme. Drug Metab. Dispos. 30(11), 1149-1152 (2002).
68. Martinez VG, O'Connor R, Liang Y, Clynes M. CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. Br. J. Cancer 98(3), 564-570 (2008).
69. Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5(10), 772-782 (2005).
70. Pardoll D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807-839 (2003).
71. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer 8(4), 299-308 (2008).
72. Vonderheide RH, June CH. A translational bridge to cancer immunotherapy: exploiting costimulation and target antigens for active and passive T cell immunotherapy. Immunol. Res. 27(2-3), 341-356 (2003).
73. Kessler JH, Melief CJ. Identification of T-cell epitopes for cancer immunotherapy. Leukemia 21(9), 1859-1874 (2007).
74. Chicz RM, Urban RG, Lane WS et al. Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size. Nature 358(6389), 764-768 (1992).
75. Singh-Jasuja H, Emmerich NP, Rammensee HG. The Tubingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy. Cancer Immunol. Immunother. 53(3), 187-195 (2004).
76. + T cells following tumor infiltration. Cancer Res. 68(8), 2993-3000 (2008).
77. McMahan RH, Slansky JE. Mobilizing the low-avidity T cell repertoire to kill tumors. Semin. Cancer Biol. 17(4), 317-329 (2007).
78. Maecker B, von Bergwelt-Baildon MS, Anderson KS et al. Rare naturally occurring immune responses to three epitopes from the widely expressed tumour antigens hTERT and CYP1B1 in multiple myeloma patients. Clin. Exp. Immunol. 141(3), 558-562 (2005).
79. Maecker B, von Bergwelt-Baildon MS, Sherr DH, Nadler LM, Schultze JL. Identification of a new HLA-A*0201-restricted cryptic epitope from CYP1B1. Int. J. Cancer 115(2), 333-336 (2005).
80. Kvistborg P, Hadrup SR, Svane IM, Andersen MH, Straten PT. Characterization of a single peptide derived from cytochrome P450 1B1 that elicits spontaneous human leukocyte antigen (HLA)-A1 as well as HLA-B35 restricted CD8 T-cell responses in cancer patients. Hum. Immunol. 69(4-5), 266-272 (2008).
81. Campoli M, Ferrone S, Zea AH, Rodriguez PC, Ochoa AC. Mechanisms of tumor evasion. Cancer Treat. Res. 123, 61-88 (2005).
82. Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol. Immunother. 56(3), 271-285 (2007).
83. Choo AY, Choo DK, Kim JJ, Weiner DB. DNA vaccination in immunotherapy of cancer. Cancer Treat. Res. 123, 137-156 (2005).
84. Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature 356(6365), 152-154 (1992).
85. Ulmer JB, Donnelly JJ, Parker SE et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259(5102), 1745-1749 (1993). • First demonstration that immunization with plasmid DNA generates a cellular immune response to the plasmid-encoded antigen.
86. Wang B, Ugen KE, Srikantan V et al. Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 90(9), 4156-4160 (1993).
87. Wolff JA, Malone RW, Williams P et al. Direct gene transfer into mouse muscle in vivo. Science 247(4949 Pt 1), 1465-1468 (1990).
88. Liu MA, Ulmer JB. Human clinical trials of plasmid DNA vaccines. Adv. Genet. 55, 25-40 (2005).
89. Ulmer JB, Wahren B, Liu MA. DNA vaccines: recent technological and clinical advances. Discov. Med. 6(33), 109-112 (2006).
90. Liniger M, Zuniga A, Naim HY. Use of viral vectors for the development of vaccines. Expert Rev. Vaccines 6(2), 255-266 (2007).
91. Slingluff CL Jr, Chianese-Bullock KA, Bullock TN et al. Immunity to melanoma antigens: from self-tolerance to immunotherapy. Adv. Immunol. 90, 243-295 (2006).
92. Pavlenko M, Roos AK, Lundqvist A et al. A Phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. Br. J. Cancer 91(4), 688-694 (2004).
93. Timmerman JM, Singh G, Hermanson G et al. Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 62(20), 5845-5852 (2002).
94. Rice J, Dunn S, Piper K et al. DNA fusion vaccines induce epitope-specific cytotoxic CD8+ T cells against human leukemia-associated minor histocompatibility antigens. Cancer Res. 66(10), 5436-5442 (2006).
95. Luxembourg A, Evans CF, Hannaman D. Electroporation-based DNA immunisation: translation to the clinic. Expert Opin. Biol. Ther. 7(11), 1647-1664 (2007).
96. Rice J, Ottensmeier CH, Stevenson FK. DNA vaccines: precision tools for activating effective immunity against cancer. Nat. Rev. Cancer 8(2), 108-120 (2008).
97. Hedley ML, Barman SP. Microparticle delivery of plasmid DNA to mammalian cells. Methods Mol. Biol. 245, 265-286 (2004).
98. O'Hagan DT, Singh M, Ulmer JB. Microparticle-based technologies for vaccines. Methods 40(1), 10-19 (2006).
99. Hedley ML. Formulations containing poly(lactide-co-glycolide) and plasmid DNA expression vectors. Expert Opin. Biol. Ther. 3(6), 903-910 (2003).
100. Hedley ML, Curley J, Urban R. Microspheres containing plasmid-encoded antigens elicit cytotoxic T-cell responses. Nat. Med. 4(3), 365-368 (1998). • Demonstration that plasmid DNA could be encapsulated in poly(lactide-co-glycolide) microparticles and that the formulation elicited cytotoxic T-cell responses to the encoded antigens.
101. Luby TM, Cole G, Baker L et al. Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1. Clin. Immunol. 112(1), 45-53 (2004).
102. Gribben JG, Ryan DP, Boyajian R et al. Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy. Clin. Cancer Res. 11(12), 4430-4436 (2005). • Describes the initial clinical trial with ZYC300, where a correlation between immunity to CYP1B1 and response to subsequent treatments was reported.
103. + regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur. J. Immunol. 34(2), 336-344 (2004).
104. Matsushita N, Pilon-Thomas SA, Martin LM, Riker AI. Comparative methodologies of regulatory T cell depletion in a murine melanoma model. J. Immunol. Methods 333(1-2), 167-179 (2008).
105. + regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56(5), 641-648 (2007).
106. Pages F, Berger A, Camus M et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353(25), 2654-2666 (2005).
107. Zhang L, Conejo-Garcia JR, Katsaros D et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348(3), 203-213 (2003).
108. + regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE 1, e129 (2006).
109. Curiel TJ, Coukos G, Zou L et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10(9), 942-949 (2004).