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*
Department of Medicine and The Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232;
Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153; and
Imperial College School of Medicine, Northwick Park Institute for Medical Research, Harrow, United Kingdom
Defective dendritic cell (DC) function caused by abnormal differentiation of these cells is an important mechanism of tumor escape from immune system control. Previously, we have demonstrated that the number and function of DC were dramatically reduced in cancer patients. This effect was closely associated with accumulation of immature cells (ImC) in peripheral blood. In this study, we investigated the nature and functional role of those ImC. Using flow cytometry, electron microscopy, colony formation assays, and cell differentiation in the presence of different cell growth factors, we have determined that the population of ImC is composed of a small percentage (<2%) of hemopoietic progenitor cells, with all other cells being represented by MHC class I-positive myeloid cells. About one-third of ImC were immature macrophages and DC, and the remaining cells were immature myeloid cells at earlier stages of differentiation. These cells were differentiated into mature DC in the presence of 1 µM all-trans-retinoic acid. Removal of ImC from DC fractions completely restored the ability of the DC to stimulate allogeneic T cells. In two different experimental systems ImC inhibited Ag-specific T cell responses. Thus, immature myeloid cells generated in large numbers in cancer patients are able to directly inhibit Ag-specific T cell responses. This may represent a new mechanism of immune suppression in cancer and may suggest a new approach to cancer treatment.
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A. Takahashi, M. G. V. Hanson, H. R. Norell, A. M. Havelka, K. Kono, K.-J. Malmberg, and R. V. R. Kiessling Preferential Cell Death of CD8+ Effector Memory (CCR7-CD45RA-) T Cells by Hydrogen Peroxide-Induced Oxidative Stress J. Immunol., May 15, 2005; 174(10): 6080 - 6087. [Abstract] [Full Text] [PDF]
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C. De Santo, P. Serafini, I. Marigo, L. Dolcetti, M. Bolla, P. Del Soldato, C. Melani, C. Guiducci, M. P. Colombo, M. Iezzi, et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination PNAS, March 15, 2005; 102(11): 4185 - 4190. [Abstract] [Full Text] [PDF]
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P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Reduction of Myeloid-Derived Suppressor Cells and Induction of M1 Macrophages Facilitate the Rejection of Established Metastatic Disease J. Immunol., January 15, 2005; 174(2): 636 - 645. [Abstract] [Full Text] [PDF]
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M. M. Dikov, J. E. Ohm, N. Ray, E. E. Tchekneva, J. Burlison, D. Moghanaki, S. Nadaf, and D. P. Carbone Differential Roles of Vascular Endothelial Growth Factor Receptors 1 and 2 in Dendritic Cell Differentiation J. Immunol., January 1, 2005; 174(1): 215 - 222. [Abstract] [Full Text] [PDF]
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 G. Gerlini, A. Tun-Kyi, C. Dudli, G. Burg, N. Pimpinelli, and F. O. Nestle Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions Am. J. Pathol., December 1, 2004; 165(6): 1853 - 1863. [Abstract] [Full Text] [PDF]
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S. Beckebaum, X. Zhang, X. Chen, Z. Yu, A. Frilling, G. Dworacki, H. Grosse-Wilde, C. E. Broelsch, G. Gerken, and V. R. Cicinnati Increased Levels of Interleukin-10 in Serum from Patients with Hepatocellular Carcinoma Correlate with Profound Numerical Deficiencies and Immature Phenotype of Circulating Dendritic Cell Subsets Clin. Cancer Res., November 1, 2004; 10(21): 7260 - 7269. [Abstract] [Full Text] [PDF]
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B. Bonnotte, M. Crittenden, N. Larmonier, M. Gough, and R. G. Vile MIP-3{alpha} Transfection into a Rodent Tumor Cell Line Increases Intratumoral Dendritic Cell Infiltration but Enhances (Facilitates) Tumor Growth and Decreases Immunogenicity J. Immunol., October 15, 2004; 173(8): 4929 - 4935. [Abstract] [Full Text] [PDF]
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 L. M. Hengesbach and K. A. Hoag Physiological Concentrations of Retinoic Acid Favor Myeloid Dendritic Cell Development over Granulocyte Development in Cultures of Bone Marrow Cells from Mice J. Nutr., October 1, 2004; 134(10): 2653 - 2659. [Abstract] [Full Text] [PDF]
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M. J. Skeen, M. M. Freeman, and H. K. Ziegler Changes in peritoneal myeloid populations and their proinflammatory cytokine expression during infection with Listeria monocytogenes are altered in the absence of {gamma}/{delta} T cells J. Leukoc. Biol., July 1, 2004; 76(1): 104 - 115. [Abstract] [Full Text] [PDF]
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P. Monti, B. E. Leone, A. Zerbi, G. Balzano, S. Cainarca, V. Sordi, M. Pontillo, A. Mercalli, V. Di Carlo, P. Allavena, et al. Tumor-Derived MUC1 Mucins Interact with Differentiating Monocytes and Induce IL-10highIL-12low Regulatory Dendritic Cell J. Immunol., June 15, 2004; 172(12): 7341 - 7349. [Abstract] [Full Text] [PDF]
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E. A. Danna, P. Sinha, M. Gilbert, V. K. Clements, B. A. Pulaski, and S. Ostrand-Rosenberg Surgical Removal of Primary Tumor Reverses Tumor-Induced Immunosuppression Despite the Presence of Metastatic Disease Cancer Res., March 15, 2004; 64(6): 2205 - 2211. [Abstract] [Full Text] [PDF]
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Q. Li, P.-Y. Pan, P. Gu, D. Xu, and S.-H. Chen Role of Immature Myeloid Gr-1+ Cells in the Development of Antitumor Immunity Cancer Res., February 1, 2004; 64(3): 1130 - 1139. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, Y. Nefedova, D. Yoder, and D. I. Gabrilovich Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species J. Immunol., January 15, 2004; 172(2): 989 - 999. [Abstract] [Full Text] [PDF]
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Y. Nefedova, M. Huang, S. Kusmartsev, R. Bhattacharya, P. Cheng, R. Salup, R. Jove, and D. Gabrilovich Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer J. Immunol., January 1, 2004; 172(1): 464 - 474. [Abstract] [Full Text] [PDF]
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V. Pisarev, B. Yu, R. Salup, S. Sherman, D. C. Altieri, and D. I. Gabrilovich Full-Length Dominant-Negative Survivin for Cancer Immunotherapy Clin. Cancer Res., December 15, 2003; 9(17): 6523 - 6533. [Abstract] [Full Text] [PDF]
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C. Melani, C. Chiodoni, G. Forni, and M. P. Colombo Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity Blood, September 15, 2003; 102(6): 2138 - 2145. [Abstract] [Full Text] [PDF]
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S. Kusmartsev, F. Cheng, B. Yu, Y. Nefedova, E. Sotomayor, R. Lush, and D. Gabrilovich All-trans-Retinoic Acid Eliminates Immature Myeloid Cells from Tumor-bearing Mice and Improves the Effect of Vaccination Cancer Res., August 1, 2003; 63(15): 4441 - 4449. [Abstract] [Full Text] [PDF]
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S. Kusmartsev and D. I. Gabrilovich Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species J. Leukoc. Biol., August 1, 2003; 74(2): 186 - 196. [Abstract] [Full Text] [PDF]
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A. D. Billiau, S. Fevery, O. Rutgeerts, W. Landuyt, and M. Waer Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions Blood, July 15, 2003; 102(2): 740 - 748. [Abstract] [Full Text] [PDF]
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Y. Liu, J. A. Van Ginderachter, L. Brys, P. De Baetselier, G. Raes, and A. B. Geldhof Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells J. Immunol., May 15, 2003; 170(10): 5064 - 5074. [Abstract] [Full Text] [PDF]
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P. Kleindienst and T. Brocker Endogenous Dendritic Cells Are Required for Amplification of T Cell Responses Induced by Dendritic Cell Vaccines In Vivo J. Immunol., March 15, 2003; 170(6): 2817 - 2823. [Abstract] [Full Text] [PDF]
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V. Bronte, P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. Sutter, et al. IL-4-Induced Arginase 1 Suppresses Alloreactive T Cells in Tumor-Bearing Mice J. Immunol., January 1, 2003; 170(1): 270 - 278. [Abstract] [Full Text] [PDF]
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B. Wirleitner, D. Reider, S. Ebner, G. Bock, B. Widner, M. Jaeger, H. Schennach, N. Romani, and D. Fuchs Monocyte-derived dendritic cells release neopterin J. Leukoc. Biol., December 1, 2002; 72(6): 1148 - 1153. [Abstract] [Full Text] [PDF]
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D. I. Gabrilovich, P. Cheng, Y. Fan, B. Yu, E. Nikitina, A. Sirotkin, M. Shurin, T. Oyama, Y. Adachi, S. Nadaf, et al. H1{degrees} histone and differentiation of dendritic cells. A molecular target for tumor-derived factors J. Leukoc. Biol., August 1, 2002; 72(2): 285 - 296. [Abstract] [Full Text] [PDF]
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 K. Mashino, N. Sadanaga, F. Tanaka, M. Ohta, H. Yamaguchi, and M. Mori Effective Strategy of Dendritic Cell-based Immunotherapy for Advanced Tumor-bearing Hosts: the Critical Role of Th1-dominant Immunity Mol. Cancer Ther., August 1, 2002; 1(10): 785 - 794. [Abstract] [Full Text] [PDF]
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T. K. Hoffmann, J. Muller-Berghaus, R. L. Ferris, J. T. Johnson, W. J. Storkus, and T. L. Whiteside Alterations in the Frequency of Dendritic Cell Subsets in the Peripheral Circulation of Patients with Squamous Cell Carcinomas of the Head and Neck Clin. Cancer Res., June 1, 2002; 8(6): 1787 - 1793. [Abstract] [Full Text] [PDF]
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C. C. Sombroek, A. G. M. Stam, A. J. Masterson, S. M. Lougheed, M. J. A. G. Schakel, C. J. L. M. Meijer, H. M. Pinedo, A. J. M. van den Eertwegh, R. J. Scheper, and T. D. de Gruijl Prostanoids Play a Major Role in the Primary Tumor-Induced Inhibition of Dendritic Cell Differentiation J. Immunol., May 1, 2002; 168(9): 4333 - 4343. [Abstract] [Full Text] [PDF]
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A. Mazzoni, V. Bronte, A. Visintin, J. H. Spitzer, E. Apolloni, P. Serafini, P. Zanovello, and D. M. Segal Myeloid Suppressor Lines Inhibit T Cell Responses by an NO-Dependent Mechanism J. Immunol., January 15, 2002; 168(2): 689 - 695. [Abstract] [Full Text] [PDF]
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D. I. Gabrilovich, M. P. Velders, E. M. Sotomayor, and W. M. Kast Mechanism of Immune Dysfunction in Cancer Mediated by Immature Gr-1+ Myeloid Cells J. Immunol., May 1, 2001; 166(9): 5398 - 5406. [Abstract] [Full Text] [PDF]
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