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Alvin J. Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
Regulatory T cells (Treg) that prevent autoimmune
diseases by suppression of self-reactive T cells may also suppress the
immune response against cancer. In mice, depletion of Treg
by Ab therapy leads to more efficient tumor rejection.
Treg-mediated suppression of antitumor immune responses may
partly explain the poor clinical response to vaccine-based
immunotherapy for human cancer. In this study, we measured the
prevalence of Treg that coexpress CD4 and CD25 in the PBLs,
tumor-infiltrating lymphocytes, and regional lymph node lymphocytes
from 65 patients with either pancreas or breast cancer. In breast
cancer patients (n = 35), pancreas cancer patients
(n = 30), and normal donors (n
= 35), the prevalence of Treg were 16.6% (SE 1.22), 13.2%
(SE 1.13), and 8.6% (SE 0.71) of the total CD4+ cells,
respectively. The prevalence of Treg were significantly
higher in breast cancer patients (p < 0.01) and
pancreas cancer patients (p < 0.01) when compared
with normal donors. In tumor-infiltrating lymphocytes and lymph node
lymphocytes, the Treg prevalence were 20.2% (SE 3.93) and
20.1% (SE 4.3), respectively. Treg constitutively
coexpressed CTLA-4 and CD45RO markers, and secreted TGF-
and IL-10
but did not secrete IFN-
. When cocultured with activated
CD8+ cells or CD4+25- cells,
Treg potently suppressed their proliferation and secretion
of IFN-. We conclude that the prevalence of Treg is
increased in the peripheral blood as well as in the tumor
microenvironment of patients with invasive breast or pancreas cancers.
These Treg may mitigate the immune response against cancer,
and may partly explain the poor immune response against tumor
Ags.
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M. Kurooka and Y. Kaneda Inactivated Sendai Virus Particles Eradicate Tumors by Inducing Immune Responses through Blocking Regulatory T Cells Cancer Res., January 1, 2007; 67(1): 227 - 236. [Abstract] [Full Text] [PDF]
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L. Strauss, T. L. Whiteside, A. Knights, C. Bergmann, A. Knuth, and A. Zippelius Selective Survival of Naturally Occurring Human CD4+CD25+Foxp3+ Regulatory T Cells Cultured with Rapamycin J. Immunol., January 1, 2007; 178(1): 320 - 329. [Abstract] [Full Text] [PDF]
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G. J. Bates, S. B. Fox, C. Han, R. D. Leek, J. F. Garcia, A. L. Harris, and A. H. Banham Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse J. Clin. Oncol., December 1, 2006; 24(34): 5373 - 5380. [Abstract] [Full Text] [PDF]
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A. M. Miller, K. Lundberg, V. Ozenci, A. H. Banham, M. Hellstrom, L. Egevad, and P. Pisa CD4+CD25high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients J. Immunol., November 15, 2006; 177(10): 7398 - 7405. [Abstract] [Full Text] [PDF]
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D. J. Powell Jr., M. E. Dudley, K. A. Hogan, J. R. Wunderlich, and S. A. Rosenberg Adoptive Transfer of Vaccine-Induced Peripheral Blood Mononuclear Cells to Patients with Metastatic Melanoma following Lymphodepletion J. Immunol., November 1, 2006; 177(9): 6527 - 6539. [Abstract] [Full Text] [PDF]
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J. Carreras, A. Lopez-Guillermo, B. C. Fox, L. Colomo, A. Martinez, G. Roncador, E. Montserrat, E. Campo, and A. H. Banham High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma Blood, November 1, 2006; 108(9): 2957 - 2964. [Abstract] [Full Text] [PDF]
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N. Hiraoka, K. Onozato, T. Kosuge, and S. Hirohashi Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions. Clin. Cancer Res., September 15, 2006; 12(18): 5423 - 5434. [Abstract] [Full Text] [PDF]
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K. L. Knutson, C. J. Krco, C. L. Erskine, K. Goodman, L. E. Kelemen, P. J. Wettstein, P. S. Low, L. C. Hartmann, and K. R. Kalli T-Cell Immunity to the Folate Receptor Alpha Is Prevalent in Women With Breast or Ovarian Cancer J. Clin. Oncol., September 10, 2006; 24(26): 4254 - 4261. [Abstract] [Full Text] [PDF]
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G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms. Clin. Cancer Res., August 15, 2006; 12(16): 4794 - 4803. [Abstract] [Full Text] [PDF]
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M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [Abstract] [Full Text] [PDF]
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J. D. Bui, R. Uppaluri, C.-S. Hsieh, and R. D. Schreiber Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins. Cancer Res., July 15, 2006; 66(14): 7301 - 7309. [Abstract] [Full Text] [PDF]
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P. E. Fecci, A. E. Sweeney, P. M. Grossi, S. K. Nair, C. A. Learn, D. A. Mitchell, X. Cui, T. J. Cummings, D. D. Bigner, E. Gilboa, et al. Systemic Anti-CD25 Monoclonal Antibody Administration Safely Enhances Immunity in Murine Glioma without Eliminating Regulatory T Cells. Clin. Cancer Res., July 15, 2006; 12(14): 4294 - 4305. [Abstract] [Full Text] [PDF]
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S. Wei, I. Kryczek, and W. Zou Regulatory T-cell compartmentalization and trafficking Blood, July 15, 2006; 108(2): 426 - 431. [Abstract] [Full Text] [PDF]
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 A. E. Andaloussi and M. S. Lesniak An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme Neuro-oncol, July 1, 2006; 8(3): 234 - 243. [Abstract] [Full Text] [PDF]
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S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, and A. B. Heimberger The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses Neuro-oncol, July 1, 2006; 8(3): 261 - 279. [Abstract] [Full Text] [PDF]
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G. Zheng, S. Liu, P. Wang, Y. Xu, and A. Chen Arming Tumor-Reactive T Cells with Costimulator B7-1 Enhances Therapeutic Efficacy of the T Cells. Cancer Res., July 1, 2006; 66(13): 6793 - 6799. [Abstract] [Full Text] [PDF]
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K. L. Knutson, Y. Dang, H. Lu, J. Lukas, B. Almand, E. Gad, E. Azeke, and M. L. Disis IL-2 Immunotoxin Therapy Modulates Tumor-Associated Regulatory T Cells and Leads to Lasting Immune-Mediated Rejection of Breast Cancers in neu-Transgenic Mice J. Immunol., July 1, 2006; 177(1): 84 - 91. [Abstract] [Full Text] [PDF]
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R. Zeiser, V. H. Nguyen, A. Beilhack, M. Buess, S. Schulz, J. Baker, C. H. Contag, and R. S. Negrin Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production Blood, July 1, 2006; 108(1): 390 - 399. [Abstract] [Full Text] [PDF]
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R. Kim, M. Emi, K. Tanabe, and K. Arihiro Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression Cancer Res., June 1, 2006; 66(11): 5527 - 5536. [Abstract] [Full Text] [PDF]
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L. Sfondrini, A. Rossini, D. Besusso, A. Merlo, E. Tagliabue, S. Menard, and A. Balsari Antitumor Activity of the TLR-5 Ligand Flagellin in Mouse Models of Cancer. J. Immunol., June 1, 2006; 176(11): 6624 - 6630. [Abstract] [Full Text] [PDF]
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R.-F. Wang Regulatory T cells and toll-like receptors in cancer therapy. Cancer Res., May 15, 2006; 66(10): 4987 - 4990. [Abstract] [Full Text] [PDF]
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M. Beyer, M. Kochanek, T. Giese, E. Endl, M. R. Weihrauch, P. A. Knolle, S. Classen, and J. L. Schultze In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma Blood, May 15, 2006; 107(10): 3940 - 3949. [Abstract] [Full Text] [PDF]
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A. Berhanu, J. Huang, S. M. Alber, S. C. Watkins, and W. J. Storkus Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy. Cancer Res., May 1, 2006; 66(9): 4895 - 4903. [Abstract] [Full Text] [PDF]
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R. Houot, I. Perrot, E. Garcia, I. Durand, and S. Lebecque Human CD4+CD25high Regulatory T Cells Modulate Myeloid but Not Plasmacytoid Dendritic Cells Activation J. Immunol., May 1, 2006; 176(9): 5293 - 5298. [Abstract] [Full Text] [PDF]
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Z.-Z. Yang, A. J. Novak, M. J. Stenson, T. E. Witzig, and S. M. Ansell Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma Blood, May 1, 2006; 107(9): 3639 - 3646. [Abstract] [Full Text] [PDF]
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B. Valzasina, S. Piconese, C. Guiducci, and M. P. Colombo Tumor-Induced Expansion of Regulatory T Cells by Conversion of CD4+CD25- Lymphocytes Is Thymus and Proliferation Independent. Cancer Res., April 15, 2006; 66(8): 4488 - 4495. [Abstract] [Full Text] [PDF]
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P. E. Fecci, D. A. Mitchell, J. F. Whitesides, W. Xie, A. H. Friedman, G. E. Archer, J. E. Herndon II, D. D. Bigner, G. Dranoff, and J. H. Sampson Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res., March 15, 2006; 66(6): 3294 - 3302. [Abstract] [Full Text] [PDF]
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G. C. Cesana, G. DeRaffele, S. Cohen, D. Moroziewicz, J. Mitcham, J. Stoutenburg, K. Cheung, C. Hesdorffer, S. Kim-Schulze, and H. L. Kaufman Characterization of CD4+CD25+ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma J. Clin. Oncol., March 1, 2006; 24(7): 1169 - 1177. [Abstract] [Full Text] [PDF]
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S. Chattopadhyay, S. Mehrotra, A. Chhabra, U. Hegde, B. Mukherji, and N. G. Chakraborty 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., January 15, 2006; 176(2): 984 - 990. [Abstract] [Full Text] [PDF]
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C. Badoual, S. Hans, J. Rodriguez, S. Peyrard, C. Klein, N. E. H. Agueznay, V. Mosseri, O. Laccourreye, P. Bruneval, W. H. Fridman, et al. Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers Clin. Cancer Res., January 15, 2006; 12(2): 465 - 472. [Abstract] [Full Text] [PDF]
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G. Zhou, C. G. Drake, and H. I. Levitsky Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines Blood, January 15, 2006; 107(2): 628 - 636. [Abstract] [Full Text] [PDF]
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A. N. Saul, T. M. Oberyszyn, C. Daugherty, D. Kusewitt, S. Jones, S. Jewell, W. B. Malarkey, A. Lehman, S. Lemeshow, and F. S. Dhabhar Chronic Stress and Susceptibility to Skin Cancer J Natl Cancer Inst, December 7, 2005; 97(23): 1760 - 1767. [Abstract] [Full Text] [PDF]
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 Y.-Q. Chen, H.-Z. Shi, X.-J. Qin, W.-N. Mo, X.-D. Liang, Z.-X. Huang, H.-B. Yang, and C. Wu CD4+CD25+ Regulatory T Lymphocytes in Malignant Pleural Effusion Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1434 - 1439. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, Q. Jiang, A. Panoskaltsis-Mortari, P. A. Taylor, K. P. McKinnon, L. Su, B. R. Blazar, and J. S. Serody Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease Blood, November 1, 2005; 106(9): 3300 - 3307. [Abstract] [Full Text] [PDF]
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F. Ghiringhelli, C. Menard, M. Terme, C. Flament, J. Taieb, N. Chaput, P. E. Puig, S. Novault, B. Escudier, E. Vivier, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-{beta}-dependent manner J. Exp. Med., October 17, 2005; 202(8): 1075 - 1085. [Abstract] [Full Text] [PDF]
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