|
|
||||||||





* Unité de Biologie Moléculaire du Gène, Institut National de la Santé et de la Recherche Médicale (INSERM) U277, Institut Pasteur,
Department of Dermatology and INSERM U532, Skin Research Institute, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris,
Department of Pathology, Hôpital Saint-Louis, and
Immunology A, Centre dÉtude et de la Recherche en Virologie et en Immunologie, Institut National de Science et Recherche Medicale, Unité 543, Hôpital Pitié-Salpetrière, Paris, France
Dominant tolerance is mediated by regulatory T cells (Treg) that control harmful autoimmune T cells in the periphery. In this study, we investigate the implication of Treg in modulating infiltrating T lymphocytes in human metastatic melanoma. We found that CD4+CD25high T cells are overrepresented in metastatic lymph nodes (LNs) with a 2-fold increased frequency compared with both tumor-free LNs and autologous PBMCs. These cells express the Foxp3 transcription factor, display an activated phenotype, and display a polyclonal TCR V
chain repertoire. They inhibit in vitro the proliferation and cytokine production of infiltrating CD4+CD25 and CD8+ T cells (IL-2, IFN-
) through a cell-contact-dependent mechanism, thus behaving as Treg. In some cases, the presence of Treg type 1/Th3-like lymphocytes could also be demonstrated. Thus, Treg are a major component of the immunosuppressive microenvironment of metastatic melanoma LNs. This could explain the poor clinical response of cancer patients under immunotherapeutic protocols, and provides a new basis for future immunotherapeutic strategies counteracting in vivo Treg to reinforce local antitumor immune responses.
Related articles in The JI:
This article has been cited by other articles:
![]() |
R. Simone, A. Zicca, and D. Saverino The frequency of regulatory CD3+CD8+CD28-CD25+ T lymphocytes in human peripheral blood increases with age J. Leukoc. Biol., December 1, 2008; 84(6): 1454 - 1461. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Larmonier, N. Janikashvili, C. J. LaCasse, C. B. Larmonier, J. Cantrell, E. Situ, T. Lundeen, B. Bonnotte, and E. Katsanis Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL- Tumors J. Immunol., November 15, 2008; 181(10): 6955 - 6963. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Koyama, H. Kagamu, S. Miura, T. Hiura, T. Miyabayashi, R. Itoh, H. Kuriyama, H. Tanaka, J. Tanaka, H. Yoshizawa, et al. Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage Clin. Cancer Res., November 1, 2008; 14(21): 6770 - 6779. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Kavanagh, S. O'Brien, D. Lee, Y. Hou, V. Weinberg, B. Rini, J. P. Allison, E. J. Small, and L. Fong CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion Blood, August 15, 2008; 112(4): 1175 - 1183. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Morse, A. C. Hobeika, T. Osada, D. Serra, D. Niedzwiecki, H. K. Lyerly, and T. M. Clay Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines Blood, August 1, 2008; 112(3): 610 - 618. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Gil-Guerrero, J. Dotor, I. L. Huibregtse, N. Casares, A. B. Lopez-Vazquez, F. Rudilla, J. I. Riezu-Boj, J. Lopez-Sagaseta, J. Hermida, S. Van Deventer, et al. In Vitro and In Vivo Down-Regulation of Regulatory T Cell Activity with a Peptide Inhibitor of TGF-{beta}1 J. Immunol., July 1, 2008; 181(1): 126 - 135. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Mittal, N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma Blood, June 1, 2008; 111(11): 5359 - 5370. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. M. Ebert, B. S. Tan, J. Browning, S. Svobodova, S. E. Russell, N. Kirkpatrick, C. Gedye, D. Moss, S. P. Ng, D. MacGregor, et al. The Regulatory T Cell-Associated Transcription Factor FoxP3 Is Expressed by Tumor Cells Cancer Res., April 15, 2008; 68(8): 3001 - 3009. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Larmonier, J. Cantrell, C. LaCasse, G. Li, N. Janikashvili, E. Situ, M. Sepassi, S. Andreansky, and E. Katsanis Chaperone-rich tumor cell lysate-mediated activation of antigen-presenting cells resists regulatory T cell suppression J. Leukoc. Biol., April 1, 2008; 83(4): 1049 - 1059. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Yokokawa, V. Cereda, C. Remondo, J. L. Gulley, P. M. Arlen, J. Schlom, and K. Y. Tsang Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer Clin. Cancer Res., February 15, 2008; 14(4): 1032 - 1040. [Abstract] [Full Text] [PDF] |
||||
![]() |
U. Berndt, L. Philipsen, S. Bartsch, B. Wiedenmann, D. C. Baumgart, M. Hammerle, and A. Sturm Systematic High-Content Proteomic Analysis Reveals Substantial Immunologic Changes in Colorectal Cancer Cancer Res., February 1, 2008; 68(3): 880 - 888. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Negin, D. Panka, W. Wang, M. Siddiqui, N. Tawa, J. Mullen, S. Tahan, L. Mandato, A. Polivy, J. Mier, et al. Effect of Melanoma on Immune Function in the Regional Lymph Node Basin Clin. Cancer Res., February 1, 2008; 14(3): 654 - 659. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Haas, L. Schopp, B. Storch-Hagenlocher, B. Fritzsching, C. Jacobi, L. Milkova, B. Fritz, A. Schwarz, E. Suri-Payer, M. Hensel, et al. Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis Blood, January 15, 2008; 111(2): 761 - 766. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Lengagne, S. Graff-Dubois, M. Garcette, L. Renia, M. Kato, J.-G. Guillet, V. H. Engelhard, M.-F. Avril, J.-P. Abastado, and A. Prevost-Blondel Distinct Role for CD8 T Cells toward Cutaneous Tumors and Visceral Metastases J. Immunol., January 1, 2008; 180(1): 130 - 137. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Vence, A. K. Palucka, J. W. Fay, T. Ito, Y.-J. Liu, J. Banchereau, and H. Ueno Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma PNAS, December 26, 2007; 104(52): 20884 - 20889. [Abstract] [Full Text] [PDF] |
||||
![]() |
Z.-W. Xia, L.-Q. Xu, W.-W. Zhong, J.-J. Wei, N.-L. Li, J. Shao, Y.-Z. Li, S.-C. Yu, and Z.-L. Zhang Heme Oxygenase-1 Attenuates Ovalbumin-Induced Airway Inflammation by Up-Regulation of Foxp3 T-Regulatory Cells, Interleukin-10, and Membrane-Bound Transforming Growth Factor- 1 Am. J. Pathol., December 1, 2007; 171(6): 1904 - 1914. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Chaput, G. Darrasse-Jeze, A.-S. Bergot, C. Cordier, S. Ngo-Abdalla, D. Klatzmann, and O. Azogui Regulatory T Cells Prevent CD8 T Cell Maturation by Inhibiting CD4 Th Cells at Tumor Sites J. Immunol., October 15, 2007; 179(8): 4969 - 4978. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. D. McCarter, J. Baumgartner, G. A. Escobar, D. Richter, K. Lewis, W. Robinson, C. Wilson, B. E. Palmer, and R. Gonzalez Immunosuppressive Dendritic and Regulatory T Cells are Upregulated in Melanoma Patients Ann. Surg. Oncol., October 1, 2007; 14(10): 2854 - 2860. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. J. Powell Jr., A. Felipe-Silva, M. J. Merino, M. Ahmadzadeh, T. Allen, C. Levy, D. E. White, S. Mavroukakis, R. J. Kreitman, S. A. Rosenberg, et al. Administration of a CD25-Directed Immunotoxin, LMB-2, to Patients with Metastatic Melanoma Induces a Selective Partial Reduction in Regulatory T Cells In Vivo J. Immunol., October 1, 2007; 179(7): 4919 - 4928. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Fazilleau, H. Bachelez, M.-L. Gougeon, and M. Viguier Cutting Edge: Size and Diversity of CD4+CD25high Foxp3+ Regulatory T Cell Repertoire in Humans: Evidence for Similarities and Partial Overlapping with CD4+CD25 T Cells J. Immunol., September 15, 2007; 179(6): 3412 - 3416. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. F. Gajewski Failure at the Effector Phase: Immune Barriers at the Level of the Melanoma Tumor Microenvironment Clin. Cancer Res., September 15, 2007; 13(18): 5256 - 5261. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. V. Johnson, C. B. Camras, and J. Kipnis Bacterial DNA Confers Neuroprotection after Optic Nerve Injury by Suppressing CD4+CD25+ Regulatory T-Cell Activity Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3441 - 3449. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Nitcheu-Tefit, M.-S. Dai, R. J. Critchley-Thorne, F. Ramirez-Jimenez, M. Xu, S. Conchon, N. Ferry, H. J. Stauss, and G. Vassaux Listeriolysin O Expressed in a Bacterial Vaccine Suppresses CD4+CD25high Regulatory T Cell Function In Vivo J. Immunol., August 1, 2007; 179(3): 1532 - 1541. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Tuve, B.-M. Chen, Y. Liu, T.-L. Cheng, P. Toure, P. S. Sow, Q. Feng, N. Kiviat, R. Strauss, S. Ni, et al. Combination of Tumor Site-Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses Cancer Res., June 15, 2007; 67(12): 5929 - 5939. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Savai, R. T. Schermuly, S. S. Pullamsetti, M. Schneider, S. Greschus, H. A. Ghofrani, H. Traupe, F. Grimminger, and G.-A. Banat A Combination Hybrid-Based Vaccination/Adoptive Cellular Therapy to Prevent Tumor Growth by Involvement of T Cells Cancer Res., June 1, 2007; 67(11): 5443 - 5453. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Holmes, G. Knudsen, S. Mackey-Cushman, and L. Su FoxP3 Enhances HIV-1 Gene Expression by Modulating NF{kappa}B Occupancy at the Long Terminal Repeat in Human T Cells J. Biol. Chem., June 1, 2007; 282(22): 15973 - 15980. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. G. Molenkamp, P. A.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 Intradermal CpG-B Activates Both Plasmacytoid and Myeloid Dendritic Cells in the Sentinel Lymph Node of Melanoma Patients Clin. Cancer Res., May 15, 2007; 13(10): 2961 - 2969. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Weishaupt, K. N. Munoz, E. Buzney, T. S. Kupper, and R. C. Fuhlbrigge T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma Clin. Cancer Res., May 1, 2007; 13(9): 2549 - 2556. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Nylen, R. Maurya, L. Eidsmo, K. D. Manandhar, S. Sundar, and D. Sacks Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis J. Exp. Med., April 16, 2007; 204(4): 805 - 817. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. P. Hilchey, A. De, L. M. Rimsza, R. B. Bankert, and S. H. Bernstein Follicular Lymphoma Intratumoral CD4+CD25+GITR+ Regulatory T Cells Potently Suppress CD3/CD28-Costimulated Autologous and Allogeneic CD8+CD25- and CD4+CD25- T Cells J. Immunol., April 1, 2007; 178(7): 4051 - 4061. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Rudge, S. P. Barrett, B. Scott, and I. R. van Driel Infiltration of a Mesothelioma by IFN-{gamma}-Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells J. Immunol., April 1, 2007; 178(7): 4089 - 4096. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. J.J. van derVliet, H. B. Koon, S. C. Yue, B. Uzunparmak, V. Seery, M. A. Gavin, A. Y. Rudensky, M. B. Atkins, S. P. Balk, and M. A. Exley Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer Clin. Cancer Res., April 1, 2007; 13(7): 2100 - 2108. [Abstract] [Full Text] [PDF] |
||||
![]() |
Q. Xu, J. Lee, E. Jankowska-Gan, J. Schultz, D. A. Roennburg, L. D. Haynes, S. Kusaka, H. W. Sollinger, S. J. Knechtle, A. M. VanBuskirk, et al. Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance J. Immunol., March 15, 2007; 178(6): 3983 - 3995. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. C. Taylor, A. Patel, K. S. Panageas, K. J. Busam, and M. S. Brady Tumor-Infiltrating Lymphocytes Predict Sentinel Lymph Node Positivity in Patients With Cutaneous Melanoma J. Clin. Oncol., March 1, 2007; 25(7): 869 - 875. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Hansson, A. O. Abdalla, A. Moshfegh, A. Choudhury, H. Rabbani, B. Nilsson, A. Osterborg, and H. Mellstedt Long-term Idiotype Vaccination Combined with Interleukin-12 (IL-12), or IL-12 and Granulocyte Macrophage Colony-Stimulating Factor, in Early-Stage Multiple Myeloma Patients Clin. Cancer Res., March 1, 2007; 13(5): 1503 - 1510. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Fozza, E. Nadal, M. Longinotti, and F. Dazzi T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25 counterpart Haematologica, February 1, 2007; 92(2): 206 - 214. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Zhang, D. Wakita, K. Chamoto, Y. Narita, N. Matsubara, H. Kitamura, and T. Nishimura Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs Int. Immunol., February 1, 2007; 19(2): 151 - 161. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Becker, M. C. Mihm, S. M. Hewitt, V. K. Sondak, J. W. Fountain, and M. Thurin Markers and Tissue Resources for Melanoma: Meeting Report. Cancer Res., November 15, 2006; 66(22): 10652 - 10657. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
L. Melencio, R. J. McKallip, H. Guan, R. Ramakrishnan, R. Jain, P. S. Nagarkatti, and M. Nagarkatti Role of CD4+CD25+ T regulatory cells in IL-2-induced vascular leak Int. Immunol., October 1, 2006; 18(10): 1461 - 1471. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Zorn and J. Ritz Studying Human Regulatory T Cells In vivo. Clin. Cancer Res., September 15, 2006; 12(18): 5265 - 5267. [Full Text] [PDF] |
||||
![]() |
L. Gazzola, C. Tincati, A. Gori, M. Saresella, I. Marventano, and F. Zanini FoxP3 mRNA Expression in Regulatory T Cells from Patients with Tuberculosis. Am. J. Respir. Crit. Care Med., August 1, 2006; 174(3): 356 - 356. [Full Text] [PDF] |
||||
![]() |
V. Appay, C. Jandus, V. Voelter, S. Reynard, S. E. Coupland, D. Rimoldi, D. Lienard, P. Guillaume, A. M. Krieg, J.-C. Cerottini, et al. New Generation Vaccine Induces Effective Melanoma-Specific CD8+ T Cells in the Circulation but Not in the Tumor Site J. Immunol., August 1, 2006; 177(3): 1670 - 1678. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Beyer and J. L. Schultze Regulatory T cells in cancer Blood, August 1, 2006; 108(3): 804 - 811. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
C. Dejaco, C. Duftner, and M. Schirmer Induction of Tolerance in Autoimmune Diseases Rather Than Cure of Cancer by Interleukin-2 Therapy J. Clin. Oncol., July 10, 2006; 24(20): e34 - e34. [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
M. Kasprzycka, M. Marzec, X. Liu, Q. Zhang, and M. A. Wasik From the Cover: Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3 PNAS, June 27, 2006; 103(26): 9964 - 9969. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
S. Danson and P. Lorigan Melanoma vaccines - they should work Ann. Onc., April 1, 2006; 17(4): 539 - 541. [Full Text] [PDF] |
||||
![]() |
T. F. Gajewski Identifying and overcoming immune resistance mechanisms in the melanoma tumor microenvironment. Clin. Cancer Res., April 1, 2006; 12(7): 2326s - 2330s. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. K. Sondak, M. S. Sabel, and J. J. Mule Allogeneic and autologous melanoma vaccines: where have we been and where are we going? Clin. Cancer Res., April 1, 2006; 12(7 Pt 2): 2337s - 2341s. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Lizee, L. G. Radvanyi, W. W. Overwijk, and P. Hwu Immunosuppression in melanoma immunotherapy: potential opportunities for intervention. Clin. Cancer Res., April 1, 2006; 12(7): 2359s - 2365s. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Miyara, Z. Amoura, C. Parizot, C. Badoual, K. Dorgham, S. Trad, M. Kambouchner, D. Valeyre, C. Chapelon-Abric, P. Debre, et al. The immune paradox of sarcoidosis and regulatory T cells J. Exp. Med., February 21, 2006; 203(2): 359 - 370. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Comes, O. Rosso, A. M. Orengo, E. Di Carlo, C. Sorrentino, R. Meazza, T. Piazza, B. Valzasina, P. Nanni, M. P. Colombo, et al. CD25+ Regulatory T Cell Depletion Augments Immunotherapy of Micrometastases by an IL-21-Secreting Cellular Vaccine J. Immunol., February 1, 2006; 176(3): 1750 - 1758. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
R. H. Prabhala, P. Neri, J. E. Bae, P. Tassone, M. A. Shammas, C. K. Allam, J. F. Daley, D. Chauhan, E. Blanchard, H. S. Thatte, et al. Dysfunctional T regulatory cells in multiple myeloma Blood, January 1, 2006; 107(1): 301 - 304. [Abstract] [Full Text] [PDF] |