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* Department of Oncology and Surgical Sciences, University of Padua, Padua, Italy;
Experimental Immunology Branch, National Cancer Institute-National Institutes of Health, Bethesda, MD;
GSF-National Research Center for Environment and Health, Institut fuer Molekulare Virologie, Muenchen, Germany;
Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
We previously demonstrated that a specialized subset of immature
myeloid cells migrate to lymphoid organs as a result of tumor growth or
immune stress, where they suppress B and T cell responses to Ags.
Although NO was required for suppression of mitogen activation of T
cells by myeloid suppressor cells (MSC), it was not required for
suppression of allogenic responses. In this study, we describe a novel
mechanism used by MSC to block T cell proliferation and CTL generation
in response to alloantigen, which is mediated by the enzyme arginase 1
(Arg1). We show that Arg1 increases superoxide production in myeloid
cells through a pathway that likely utilizes the reductase domain of
inducible NO synthase (iNOS), and that superoxide is required for
Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4
in freshly isolated MSC or cloned MSC lines, and is therefore
up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is
induced by IFN-
and Th1 cells. Because Arg1 and iNOS share
L-arginine as a common substrate, our results indicate that
L-arginine metabolism in myeloid cells is a potential
target for selective intervention in reversing myeloid-induced
dysfunction in tumor-bearing hosts.
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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]
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I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S. Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma J. Exp. Med., April 17, 2006; 203(4): 871 - 881. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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P. C. Rodriguez, C. P. Hernandez, D. Quiceno, S. M. Dubinett, J. Zabaleta, J. B. Ochoa, J. Gilbert, and A. C. Ochoa Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. Exp. Med., October 3, 2005; 202(7): 931 - 939. [Abstract] [Full Text] [PDF]
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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]
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L. Brys, A. Beschin, G. Raes, G. H. Ghassabeh, W. Noel, J. Brandt, F. Brombacher, and P. D. Baetselier Reactive Oxygen Species and 12/15-Lipoxygenase Contribute to the Antiproliferative Capacity of Alternatively Activated Myeloid Cells Elicited during Helminth Infection J. Immunol., May 15, 2005; 174(10): 6095 - 6104. [Abstract] [Full Text] [PDF]
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V. Bronte, T. Kasic, G. Gri, K. Gallana, G. Borsellino, I. Marigo, L. Battistini, M. Iafrate, T. Prayer-Galetti, F. Pagano, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers J. Exp. Med., April 18, 2005; 201(8): 1257 - 1268. [Abstract] [Full Text] [PDF]
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A. H. Zea, P. C. Rodriguez, M. B. Atkins, C. Hernandez, S. Signoretti, J. Zabaleta, D. McDermott, D. Quiceno, A. Youmans, A. O'Neill, et al. Arginase-Producing Myeloid Suppressor Cells in Renal Cell Carcinoma Patients: A Mechanism of Tumor Evasion Cancer Res., April 15, 2005; 65(8): 3044 - 3048. [Abstract] [Full Text] [PDF]
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S. Kusmartsev and D. I. Gabrilovich STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion J. Immunol., April 15, 2005; 174(8): 4880 - 4891. [Abstract] [Full Text] [PDF]
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 A. Astolfi, L. Landuzzi, G. Nicoletti, C. De Giovanni, S. Croci, A. Palladini, S. Ferrini, M. Iezzi, P. Musiani, F. Cavallo, et al. Gene Expression Analysis of Immune-Mediated Arrest of Tumorigenesis in a Transgenic Mouse Model of HER-2/neu-Positive Basal-Like Mammary Carcinoma Am. J. Pathol., April 1, 2005; 166(4): 1205 - 1216. [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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M. Munder, F. Mollinedo, J. Calafat, J. Canchado, C. Gil-Lamaignere, J. M. Fuentes, C. Luckner, G. Doschko, G. Soler, K. Eichmann, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity Blood, March 15, 2005; 105(6): 2549 - 2556. [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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P. Serafini, R. Carbley, K. A. Noonan, G. Tan, V. Bronte, and I. Borrello High-Dose Granulocyte-Macrophage Colony-Stimulating Factor-Producing Vaccines Impair the Immune Response through the Recruitment of Myeloid Suppressor Cells Cancer Res., September 1, 2004; 64(17): 6337 - 6343. [Abstract] [Full Text] [PDF]
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P. C. Rodriguez, D. G. Quiceno, J. Zabaleta, B. Ortiz, A. H. Zea, M. B. Piazuelo, A. Delgado, P. Correa, J. Brayer, E. M. Sotomayor, et al. Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses Cancer Res., August 15, 2004; 64(16): 5839 - 5849. [Abstract] [Full Text] [PDF]
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P. C. Rodriguez, A. H. Zea, J. DeSalvo, K. S. Culotta, J. Zabaleta, D. G. Quiceno, J. B. Ochoa, and A. C. Ochoa L-Arginine Consumption by Macrophages Modulates the Expression of CD3{zeta} Chain in T Lymphocytes J. Immunol., August 1, 2003; 171(3): 1232 - 1239. [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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