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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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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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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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