|
|
||||||||






*
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.
This article has been cited by other articles:
![]() |
G. Willimsky, M. Czeh, C. Loddenkemper, J. Gellermann, K. Schmidt, P. Wust, H. Stein, and T. Blankenstein Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness J. Exp. Med., July 7, 2008; 205(7): 1687 - 1700. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. I. Daud, N. Mirza, B. Lenox, S. Andrews, P. Urbas, G. X. Gao, J.-H. Lee, V. K. Sondak, A. I. Riker, R. C. DeConti, et al. Phenotypic and Functional Analysis of Dendritic Cells and Clinical Outcome in Patients With High-Risk Melanoma Treated With Adjuvant Granulocyte Macrophage Colony-Stimulating Factor J. Clin. Oncol., July 1, 2008; 26(19): 3235 - 3241. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. J. Gough, C. E. Ruby, W. L. Redmond, B. Dhungel, A. Brown, and A. D. Weinberg OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor Cancer Res., July 1, 2008; 68(13): 5206 - 5215. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. A. Sosman, C. Carrillo, W. J. Urba, L. Flaherty, M. B. Atkins, J. I. Clark, J. Dutcher, K. A. Margolin, J. Mier, J. Gollob, et al. Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2-Positive Advanced Melanoma J. Clin. Oncol., May 10, 2008; 26(14): 2292 - 2298. [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] |
||||
![]() |
P.-Y. Pan, G. X. Wang, B. Yin, J. Ozao, T. Ku, C. M. Divino, and S.-H. Chen Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function Blood, January 1, 2008; 111(1): 219 - 228. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Duluc, Y. Delneste, F. Tan, M.-P. Moles, L. Grimaud, J. Lenoir, L. Preisser, I. Anegon, L. Catala, N. Ifrah, et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells Blood, December 15, 2007; 110(13): 4319 - 4330. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Nefedova, M. Fishman, S. Sherman, X. Wang, A. A. Beg, and D. I. Gabrilovich Mechanism of All-Trans Retinoic Acid Effect on Tumor-Associated Myeloid-Derived Suppressor Cells Cancer Res., November 15, 2007; 67(22): 11021 - 11028. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. C. Kousis, B. W. Henderson, P. G. Maier, and S. O. Gollnick Photodynamic Therapy Enhancement of Antitumor Immunity Is Regulated by Neutrophils Cancer Res., November 1, 2007; 67(21): 10501 - 10510. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. K. Bunt, L. Yang, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression Cancer Res., October 15, 2007; 67(20): 10019 - 10026. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Ferretti, A. Felici, F. Cognetti, and M. Mandala Transforming Growth Factor-{beta} Signaling and Regulatory T Cells J. Clin. Oncol., October 10, 2007; 25(29): 4695 - 4696. [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] |
||||
![]() |
C. E. Clark, S. R. Hingorani, R. Mick, C. Combs, D. A. Tuveson, and R. H. Vonderheide Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion Cancer Res., October 1, 2007; 67(19): 9518 - 9527. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Darmanin, J. Chen, S. Zhao, H. Cui, R. Shirkoohi, N. Kubo, Y. Kuge, N. Tamaki, K. Nakagawa, J.-i. Hamada, et al. All-trans Retinoic Acid Enhances Murine Dendritic Cell Migration to Draining Lymph Nodes via the Balance of Matrix Metalloproteinases and Their Inhibitors J. Immunol., October 1, 2007; 179(7): 4616 - 4625. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. Fricke, N. Mirza, J. Dupont, C. Lockhart, A. Jackson, J.-H. Lee, J. A. Sosman, and D. I. Gabrilovich Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses Clin. Cancer Res., August 15, 2007; 13(16): 4840 - 4848. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Sinha, V. K. Clements, S. K. Bunt, S. M. Albelda, and S. Ostrand-Rosenberg Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response J. Immunol., July 15, 2007; 179(2): 977 - 983. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Huang, X. Chen, M. M. Dikov, S. V. Novitskiy, C. A. Mosse, L. Yang, and D. P. Carbone Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF Blood, July 15, 2007; 110(2): 624 - 631. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Filipazzi, R. Valenti, V. Huber, L. Pilla, P. Canese, M. Iero, C. Castelli, L. Mariani, G. Parmiani, and L. Rivoltini Identification of a New Subset of Myeloid Suppressor Cells in Peripheral Blood of Melanoma Patients With Modulation by a Granulocyte-Macrophage Colony-Stimulation Factor-Based Antitumor Vaccine J. Clin. Oncol., June 20, 2007; 25(18): 2546 - 2553. [Abstract] [Full Text] [PDF] |
||||
![]() |
U. Bharadwaj, M. Li, R. Zhang, C. Chen, and Q. Yao Elevated Interleukin-6 and G-CSF in Human Pancreatic Cancer Cell Conditioned Medium Suppress Dendritic Cell Differentiation and Activation Cancer Res., June 1, 2007; 67(11): 5479 - 5488. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells Cancer Res., May 1, 2007; 67(9): 4507 - 4513. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Faith, E. Peek, J. McDonald, Z. Urry, D. F. Richards, C. Tan, G. Santis, and C. Hawrylowicz Plasmacytoid Dendritic Cells from Human Lung Cancer Draining Lymph Nodes Induce Tc1 Responses Am. J. Respir. Cell Mol. Biol., March 1, 2007; 36(3): 360 - 367. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Vieweg, Z. Su, P. Dahm, and S. Kusmartsev Reversal of Tumor-Mediated Immunosuppression Clin. Cancer Res., January 15, 2007; 13(2): 727s - 732s. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. A. Sosman, I. Puzanov, and M. B. Atkins Opportunities and Obstacles to Combination Targeted Therapy in Renal Cell Cancer Clin. Cancer Res., January 15, 2007; 13(2): 764s - 769s. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Yanagisawa, M. A. Exley, X. Jiang, N. Ohkochi, M. Taniguchi, and K.-i. Seino Hyporesponsiveness to Natural Killer T-Cell Ligand {alpha}-Galactosylceramide in Cancer-Bearing State Mediated by CD11b+ Gr-1+ Cells Producing Nitric Oxide Cancer Res., December 1, 2006; 66(23): 11441 - 11446. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. R. Gabri, Z. Mazorra, G. V. Ripoll, C. Mesa, L. E. Fernandez, D. E. Gomez, and D. F. Alonso Complete Antitumor Protection by Perioperative Immunization with GM3/VSSP Vaccine in a Preclinical Mouse Melanoma Model Clin. Cancer Res., December 1, 2006; 12(23): 7092 - 7098. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. M. Hargadon, C. C. Brinkman, S. L. Sheasley-O'Neill, L. A. Nichols, T. N. J. Bullock, and V. H. Engelhard Incomplete Differentiation of Antigen-Specific CD8 T Cells in Tumor-Draining Lymph Nodes J. Immunol., November 1, 2006; 177(9): 6081 - 6090. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Mirza, M. Fishman, I. Fricke, M. Dunn, A. M. Neuger, T. J. Frost, R. M. Lush, S. Antonia, and D. I. Gabrilovich All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer Patients. Cancer Res., September 15, 2006; 66(18): 9299 - 9307. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
K. C. McKenna and J. A. Kapp Accumulation of Immunosuppressive CD11b+ Myeloid Cells Correlates with the Failure to Prevent Tumor Growth in the Anterior Chamber of the Eye J. Immunol., August 1, 2006; 177(3): 1599 - 1608. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. A. Van Ginderachter, S. Meerschaut, Y. Liu, L. Brys, K. De Groeve, G. Hassanzadeh Ghassabeh, G. Raes, and P. De Baetselier Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer Blood, July 15, 2006; 108(2): 525 - 535. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Yang, Z. Cai, Y. Zhang, W. H. Yutzy IV, K. F. Roby, and R. B.S. Roden CD80 in Immune Suppression by Mouse Ovarian Carcinoma-Associated Gr-1+CD11b+ Myeloid Cells. Cancer Res., July 1, 2006; 66(13): 6807 - 6815. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
Z. F. M. Vasconcelos, B. M. dos Santos, J. Farache, T. S. S. Palmeira, R. B. Areal, J. M. T. Cunha, M. A. Barcinski, and A. Bonomo G-CSF-treated granulocytes inhibit acute graft-versus-host disease Blood, March 1, 2006; 107(5): 2192 - 2199. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Huang, P.-Y. Pan, Q. Li, A. I. Sato, D. E. Levy, J. Bromberg, C. M. Divino, and S.-H. Chen Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host Cancer Res., January 15, 2006; 66(2): 1123 - 1131. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. K. Bunt, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression J. Immunol., January 1, 2006; 176(1): 284 - 290. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Interleukin-13-regulated M2 Macrophages in Combination with Myeloid Suppressor Cells Block Immune Surveillance against Metastasis Cancer Res., December 15, 2005; 65(24): 11743 - 11751. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Kusmartsev, S. Nagaraj, and D. I. Gabrilovich Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells J. Immunol., October 1, 2005; 175(7): 4583 - 4592. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Suzuki, V. Kapoor, A. S. Jassar, L. R. Kaiser, and S. M. Albelda Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity Clin. Cancer Res., September 15, 2005; 11(18): 6713 - 6721. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Fauriat, A. Moretta, D. Olive, and R. T. Costello Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients Blood, September 15, 2005; 106(6): 2186 - 2188. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. P. Carbone, I. F. Ciernik, M. J. Kelley, M. C. Smith, S. Nadaf, D. Kavanaugh, V. E. Maher, M. Stipanov, D. Contois, B. E. Johnson, et al. Immunization With Mutant p53- and K-ras-Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome J. Clin. Oncol., August 1, 2005; 23(22): 5099 - 5107. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Rughetti, I. Pellicciotta, M. Biffoni, M. Backstrom, T. Link, E. P. Bennet, H. Clausen, T. Noll, G. C. Hansson, J. M. Burchell, et al. Recombinant Tumor-Associated MUC1 Glycoprotein Impairs the Differentiation and Function of Dendritic Cells J. Immunol., June 15, 2005; 174(12): 7764 - 7772. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
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] |
||||