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*
Department of Oncology and Surgical Sciences, Padua, Italy;
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814; and
Surgery Branch, National Institutes of Health, Bethesda, MD 20892
Tumor cells gene-modified to produce GM-CSF potently stimulate
antitumor immune responses, in part, by causing the growth and
differentiation of dendritic cells (DC). However, GM-CSF-modified tumor
cells must be 
-irradiated or they will grow progressively, killing
the host. We observed that 23 of 75 (31%) human tumor lines and two
commonly used mouse tumor lines spontaneously produced GM-CSF. In mice,
chronic GM-CSF production by tumors suppressed Ag-specific
CD8+ T cell responses. Interestingly, an inhibitory
population of adherent CD11b(Mac-1)/Gr-1 double-positive cells caused
the observed impairment of CD8+ T cell function upon direct
cell-to-cell contact. The inhibitory cells were positive for some
markers associated with Ag presenting cells, like F4/80, but were
negative for markers associated with fully mature DC like DEC205, B7.2,
and MHC class II. We have previously reported that a similar or
identical population of inhibitory "immature" APC was elicited
after immunization with powerful recombinant immunogens. We show here
that these inhibitory cells can be elicited by the administration of
recombinant GM-CSF alone, and, furthermore, that they can be
differentiated ex vivo into "mature" APC by the addition of IL-4
and GM-CSF. Thus, tumors may be able to escape from immune detection by
producing "unopposed" GM-CSF, thereby disrupting the balance of
cytokines needed for the maturation of fully functional DC. Further,
CD11b/Gr-1 double-positive cells may function as "inhibitory" APC
under the influence of GM-CSF alone.
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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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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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G. Gri, E. Gallo, E. Di Carlo, P. Musiani, and M. P. Colombo OX40 Ligand-Transduced Tumor Cell Vaccine Synergizes with GM-CSF and Requires CD40-Apc Signaling to Boost the Host T Cell Antitumor Response J. Immunol., January 1, 2003; 170(1): 99 - 106. [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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A. B. Geldhof, J. A. Van Ginderachter, Y. Liu, W. Noel, G. Raes, and P. De Baetselier Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation Blood, December 1, 2002; 100(12): 4049 - 4058. [Abstract] [Full Text] [PDF]
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G. Miller, V. G. Pillarisetty, A. B. Shah, S. Lahrs, Z. Xing, and R. P. DeMatteo Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Overexpression In Vivo Results in the Long-Term Recruitment of a Distinct Dendritic Cell Population with Enhanced Immunostimulatory Function J. Immunol., September 15, 2002; 169(6): 2875 - 2885. [Abstract] [Full Text] [PDF]
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A. Mencacci, C. Montagnoli, A. Bacci, E. Cenci, L. Pitzurra, A. Spreca, M. Kopf, A. H. Sharpe, and L. Romani CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis J. Immunol., September 15, 2002; 169(6): 3180 - 3190. [Abstract] [Full Text] [PDF]
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H. J. Bontkes, T. D. de Gruijl, G. J. Schuurhuis, R. J. Scheper, C. J. L. M. Meijer, and E. Hooijberg Expansion of dendritic cell precursors from human CD34+ progenitor cells isolated from healthy donor blood; growth factor combination determines proliferation rate and functional outcome J. Leukoc. Biol., August 1, 2002; 72(2): 321 - 329. [Abstract] [Full Text] [PDF]
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E. Padovan, L. Terracciano, U. Certa, B. Jacobs, A. Reschner, M. Bolli, G. C. Spagnoli, E. C. Borden, and M. Heberer Interferon Stimulated Gene 15 Constitutively Produced by Melanoma Cells Induces E-Cadherin Expression on Human Dendritic Cells Cancer Res., June 1, 2002; 62(12): 3453 - 3458. [Abstract] [Full Text] [PDF]
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R. D. Blumenthal, A. Reising, E. Leon, and D. M. Goldenberg Modulation of Marrow Proliferation and Chemosensitivity by Tumor-produced Cytokines from Syngeneic Pancreatic Tumor Lines Clin. Cancer Res., May 1, 2002; 8(5): 1301 - 1309. [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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L. I. Terrazas, K. L. Walsh, D. Piskorska, E. McGuire, and D. A. Harn Jr. The Schistosome Oligosaccharide Lacto-N-neotetraose Expands Gr1+ Cells That Secrete Anti-inflammatory Cytokines and Inhibit Proliferation of Naive CD4+ Cells: A Potential Mechanism for Immune Polarization in Helminth Infections J. Immunol., November 1, 2001; 167(9): 5294 - 5303. [Abstract] [Full Text] [PDF]
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O. Atochina, T. Daly-Engel, D. Piskorska, E. McGuire, and D. A. Harn A Schistosome-Expressed Immunomodulatory Glycoconjugate Expands Peritoneal Gr1+ Macrophages That Suppress Naive CD4+ T Cell Proliferation Via an IFN-{gamma} and Nitric Oxide-Dependent Mechanism J. Immunol., October 15, 2001; 167(8): 4293 - 4302. [Abstract] [Full Text] [PDF]
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A. Mann, K. Breuhahn, P. Schirmacher, A. Wilhelmi, C. Beyer, A. Rosenau, S. Özbek, S. Rose-John, and M. Blessing Up- and Down-Regulation of Granulocyte/Macrophage-Colony Stimulating Factor Activity in Murine Skin Increase Susceptibility to Skin Carcinogenesis by Independent Mechanisms Cancer Res., March 1, 2001; 61(5): 2311 - 2319. [Abstract] [Full Text]
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E. Apolloni, V. Bronte, A. Mazzoni, P. Serafini, A. Cabrelle, D. M. Segal, H. A. Young, and P. Zanovello Immortalized Myeloid Suppressor Cells Trigger Apoptosis in Antigen-Activated T Lymphocytes J. Immunol., December 15, 2000; 165(12): 6723 - 6730. [Abstract] [Full Text] [PDF]
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V. Bronte, E. Apolloni, A. Cabrelle, R. Ronca, P. Serafini, P. Zamboni, N. P. Restifo, and P. Zanovello Identification of a CD11b+/Gr-1+/CD31+ myeloid progenitor capable of activating or suppressing CD8+ T cells Blood, December 1, 2000; 96(12): 3838 - 3846. [Abstract] [Full Text] [PDF]
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S. A. Kusmartsev, Y. Li, and S.-H. Chen Gr-1+ Myeloid Cells Derived from Tumor-Bearing Mice Inhibit Primary T Cell Activation Induced Through CD3/CD28 Costimulation J. Immunol., July 15, 2000; 165(2): 779 - 785. [Abstract] [Full Text] [PDF]
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E. Daro, B. Pulendran, K. Brasel, M. Teepe, D. Pettit, D. H. Lynch, D. Vremec, L. Robb, K. Shortman, H. J. McKenna, et al. Polyethylene Glycol-Modified GM-CSF Expands CD11bhighCD11chigh But Not CD11blowCD11chigh Murine Dendritic Cells In Vivo: A Comparative Analysis with Flt3 Ligand J. Immunol., July 1, 2000; 165(1): 49 - 58. [Abstract] [Full Text] [PDF]
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M. Graner, A. Raymond, D. Romney, L. He, L. Whitesell, and E. Katsanis Immunoprotective Activities of Multiple Chaperone Proteins Isolated from Murine B-Cell Leukemia/Lymphoma Clin. Cancer Res., March 1, 2000; 6(3): 909 - 915. [Abstract] [Full Text]
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S. Salvadori, G. Martinelli, and K. Zier Resection of Solid Tumors Reverses T Cell Defects and Restores Protective Immunity J. Immunol., February 15, 2000; 164(4): 2214 - 2220. [Abstract] [Full Text] [PDF]
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