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The Journal of Immunology, 2002, 168: 4272-4276.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation1

Edward Y. Woo2,{dagger}, Heidi Yeh2,{dagger}, Christina S. Chu{ddagger}, Katia Schlienger*, Richard G. Carroll*, James L. Riley*, Larry R. Kaiser{dagger} and Carl H. June3,*

* Abramson Family Cancer Research Institute and Departments of {dagger} Surgery and {ddagger} Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, PA 19104

Active suppression by T regulatory cells plays an important role in the down-regulation of T cell responses to foreign and self-Ags. Thus far, the potential role of CD4+CD25+ T cells in human tumors has not been reported. In this work we show that lung tumors contain large numbers of these cells and that they have constitutive high-level expression of CD152 (CTLA-4). Furthermore, the CD4+CD25+ T cells mediate potent inhibition of autologous T cell proliferation. Finally, regulatory T cells from patient tumors failed to inhibit the proliferation of allogeneic T cells. Together these results suggest that the CD4+CD25+ T cells found in lung tumors selectively inhibit the host immune response and therefore could contribute to the progression of lung cancer.




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S. Gnjatic
Immunogenic Targets in Non-Small Cell Lung Cancer: More Is More
Clin. Cancer Res., August 1, 2005; 11(15): 5331 - 5332.
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 Cancer Res.Home page
S. Sharma, S.-C. Yang, L. Zhu, K. Reckamp, B. Gardner, F. Baratelli, M. Huang, R. K. Batra, and S. M. Dubinett
Tumor Cyclooxygenase-2/Prostaglandin E2-Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer
Cancer Res., June 15, 2005; 65(12): 5211 - 5220.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. Kudo-Saito, J. Schlom, K. Camphausen, C. N. Coleman, and J. W. Hodge
The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors
Clin. Cancer Res., June 15, 2005; 11(12): 4533 - 4544.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
K. Liu, S. A. Caldwell, and S. I. Abrams
Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequences of Fas-Mediated Cytotoxicity and Altered IFN-{gamma}-Regulated Gene Expression
Cancer Res., May 15, 2005; 65(10): 4376 - 4388.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
L. A. Ormandy, T. Hillemann, H. Wedemeyer, M. P. Manns, T. F. Greten, and F. Korangy
Increased Populations of Regulatory T Cells in Peripheral Blood of Patients with Hepatocellular Carcinoma
Cancer Res., March 15, 2005; 65(6): 2457 - 2464.
[Abstract] [Full Text] [PDF]

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 JEMHome page
P. Yu, Y. Lee, W. Liu, T. Krausz, A. Chong, H. Schreiber, and Y.-X. Fu
Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors
J. Exp. Med., March 7, 2005; 201(5): 779 - 791.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. Y. Wang, G. Peng, Z. Guo, E. M. Shevach, and R.-F. Wang
Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells
J. Immunol., March 1, 2005; 174(5): 2661 - 2670.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
A. Lundgren, E. Stromberg, A. Sjoling, C. Lindholm, K. Enarsson, A. Edebo, E. Johnsson, E. Suri-Payer, P. Larsson, A. Rudin, et al.
Mucosal FOXP3-Expressing CD4+ CD25high Regulatory T Cells in Helicobacter pylori-Infected Patients
Infect. Immun., January 1, 2005; 73(1): 523 - 531.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. L. Riley and C. H. June
The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation
Blood, January 1, 2005; 105(1): 13 - 21.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
B. T. Rouse and S. Suvas
Regulatory Cells and Infectious Agents: Detentes Cordiale and Contraire
J. Immunol., August 15, 2004; 173(4): 2211 - 2215.
[Abstract] [Full Text] [PDF]

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 ThoraxHome page
D S Robinson
Regulation: the art of control? Regulatory T cells and asthma and allergy
Thorax, August 1, 2004; 59(8): 640 - 643.
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 JCOHome page
L. E. Raez, P. A. Cassileth, J. J. Schlesselman, K. Sridhar, S. Padmanabhan, E. Z. Fisher, P. A. Baldie, and E. R. Podack
Allogeneic Vaccination With a B7.1 HLA-A Gene-Modified Adenocarcinoma Cell Line in Patients With Advanced Non-Small-Cell Lung Cancer
J. Clin. Oncol., July 15, 2004; 22(14): 2800 - 2807.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
M. Viguier, F. Lemaitre, O. Verola, M.-S. Cho, G. Gorochov, L. Dubertret, H. Bachelez, P. Kourilsky, and L. Ferradini
Foxp3 Expressing CD4+CD25high Regulatory T Cells Are Overrepresented in Human Metastatic Melanoma Lymph Nodes and Inhibit the Function of Infiltrating T Cells
J. Immunol., July 15, 2004; 173(2): 1444 - 1453.
[Abstract] [Full Text] [PDF]

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 ScienceHome page
J. N. Blattman and P. D. Greenberg
Cancer Immunotherapy: A Treatment for the Masses
Science, July 9, 2004; 305(5681): 200 - 205.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
Y. Sasaki, M. Sakai, S. Miyazaki, S. Higuma, A. Shiozaki, and S. Saito
Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases
Mol. Hum. Reprod., May 1, 2004; 10(5): 347 - 353.
[Abstract] [Full Text] [PDF]

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 JCOHome page
M. Y. Mapara and M. Sykes
Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance
J. Clin. Oncol., March 15, 2004; 22(6): 1136 - 1151.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
E. M. Aandahl, J. Michaelsson, W. J. Moretto, F. M. Hecht, and D. F. Nixon
Human CD4+ CD25+ Regulatory T Cells Control T-Cell Responses to Human Immunodeficiency Virus and Cytomegalovirus Antigens
J. Virol., March 1, 2004; 78(5): 2454 - 2459.
[Abstract] [Full Text] [PDF]

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 JEMHome page
J. Huehn, K. Siegmund, J. C.U. Lehmann, C. Siewert, U. Haubold, M. Feuerer, G. F. Debes, J. Lauber, O. Frey, G. K. Przybylski, et al.
Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells
J. Exp. Med., February 2, 2004; 199(3): 303 - 313.
[Abstract] [Full Text] [PDF]

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 JEMHome page
W. Chen, W. Jin, N. Hardegen, K.-j. Lei, L. Li, N. Marinos, G. McGrady, and S. M. Wahl
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., December 15, 2003; 198(12): 1875 - 1886.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
J. Li, P. Hu, L. A. Khawli, and A. L. Epstein
Complete Regression of Experimental Solid Tumors by Combination LEC/chTNT-3 Immunotherapy and CD25+ T-Cell Depletion
Cancer Res., December 1, 2003; 63(23): 8384 - 8392.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
A. Cavani, F. Nasorri, C. Ottaviani, S. Sebastiani, O. De Pita, and G. Girolomoni
Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals
J. Immunol., December 1, 2003; 171(11): 5760 - 5768.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
K. J. Young, L. S. Kay, M. J. Phillips, and L. Zhang
Antitumor Activity Mediated by Double-Negative T Cells
Cancer Res., November 15, 2003; 63(22): 8014 - 8021.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
F. Ichihara, K. Kono, A. Takahashi, H. Kawaida, H. Sugai, and H. Fujii
Increased Populations of Regulatory T Cells in Peripheral Blood and Tumor-Infiltrating Lymphocytes in Patients with Gastric and Esophageal Cancers
Clin. Cancer Res., October 1, 2003; 9(12): 4404 - 4408.
[Abstract] [Full Text] [PDF]

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 BloodHome page
G. G. Laport, B. L. Levine, E. A. Stadtmauer, S. J. Schuster, S. M. Luger, S. Grupp, N. Bunin, F. J. Strobl, J. Cotte, Z. Zheng, et al.
Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation
Blood, September 15, 2003; 102(6): 2004 - 2013.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
G. Q. Phan, J. C. Yang, R. M. Sherry, P. Hwu, S. L. Topalian, D. J. Schwartzentruber, N. P. Restifo, L. R. Haworth, C. A. Seipp, L. J. Freezer, et al.
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
PNAS, July 8, 2003; 100(14): 8372 - 8377.
[Abstract] [Full Text] [PDF]

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 BloodHome page
K. Sato, N. Yamashita, M. Baba, and T. Matsuyama
Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells
Blood, May 1, 2003; 101(9): 3581 - 3589.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. Bonnefoix, P. Bonnefoix, J.-Q. Mi, J.-J. Lawrence, J.-J. Sotto, and D. Leroux
Detection of Suppressor T Lymphocytes and Estimation of Their Frequency in Limiting Dilution Assays by Generalized Linear Regression Modeling
J. Immunol., March 15, 2003; 170(6): 2884 - 2894.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
R. K. Batra, Y. Lin, S. Sharma, M. Dohadwala, J. Luo, M. Pold, and S. M. Dubinett
Non-Small Cell Lung Cancer-derived Soluble Mediators Enhance Apoptosis in Activated T Lymphocytes through an I{kappa}B Kinase-dependent Mechanism
Cancer Res., February 1, 2003; 63(3): 642 - 646.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. M. Wolf, D. Wolf, M. Steurer, G. Gastl, E. Gunsilius, and B. Grubeck-Loebenstein
Increase of Regulatory T Cells in the Peripheral Blood of Cancer Patients
Clin. Cancer Res., February 1, 2003; 9(2): 606 - 612.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
W.-P. Min, D. Zhou, T. E. Ichim, G. H. Strejan, X. Xia, J. Yang, X. Huang, B. Garcia, D. White, P. Dutartre, et al.
Inhibitory Feedback Loop Between Tolerogenic Dendritic Cells and Regulatory T Cells in Transplant Tolerance
J. Immunol., February 1, 2003; 170(3): 1304 - 1312.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. J. Moran, D. A. Arenberg, C.-C. Huang, T. J. Giordano, D. G. Thomas, D. E. Misek, G. Chen, M. D. Iannettoni, M. B. Orringer, S. Hanash, et al.
RANTES Expression Is a Predictor of Survival in Stage I Lung Adenocarcinoma
Clin. Cancer Res., December 1, 2002; 8(12): 3803 - 3812.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
R. Somasundaram, L. Jacob, R. Swoboda, L. Caputo, H. Song, S. Basak, D. Monos, D. Peritt, F. Marincola, D. Cai, et al.
Inhibition of Cytolytic T Lymphocyte Proliferation by Autologous CD4+/CD25+ Regulatory T Cells in a Colorectal Carcinoma Patient Is Mediated by Transforming Growth Factor-{beta}
Cancer Res., September 15, 2002; 62(18): 5267 - 5272.
[Abstract] [Full Text] [PDF]


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