Impaired gp100-Specific CD8+ T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model

Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In th...

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Published in:Journal of investigative dermatology 2015-11, Vol.135 (11), p.2785-2793
Main Authors: Mairhofer, David G., Ortner, Daniela, Tripp, Christoph H., Schaffenrath, Sandra, Fleming, Viktor, Heger, Lukas, Komenda, Kerstin, Reider, Daniela, Dudziak, Diana, Chen, Suzie, Becker, Jürgen C., Flacher, Vincent, Stoitzner, Patrizia
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
CD8-Positive T-Lymphocytes - immunology
Cell Proliferation
Disease Models, Animal
gp100 Melanoma Antigen - immunology
gp100 Melanoma Antigen - metabolism
Humans
Immunology
Life Sciences
Lymphocyte Activation
Melanoma, Experimental - immunology
Melanoma, Experimental - pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Original
Random Allocation
Suppressor Factors, Immunologic - immunology
Suppressor Factors, Immunologic - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Tumor Cells, Cultured
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cited_by cdi_FETCH-LOGICAL-c563t-b4fd22b6f03dead13948b02789188b163f4eff71bae941830bf1a79a4fb4d04d3
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creator Mairhofer, David G.
Ortner, Daniela
Tripp, Christoph H.
Schaffenrath, Sandra
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Reider, Daniela
Dudziak, Diana
Chen, Suzie
Becker, Jürgen C.
Flacher, Vincent
Stoitzner, Patrizia
description Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4+ T cells including regulatory T cells (Tregs) in CD45+ leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8+ T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8+ T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSCs) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSCs) over monocytic MDSC (moMDSCs). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS), and transforming growth factor-β and suppressed T-cell proliferation in vitro. In this work, we describe the immune status of a spontaneous melanoma mouse model that provides an interesting tool to develop future immunotherapeutical strategies.
doi_str_mv 10.1038/jid.2015.241
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The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4+ T cells including regulatory T cells (Tregs) in CD45+ leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8+ T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8+ T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSCs) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSCs) over monocytic MDSC (moMDSCs). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS), and transforming growth factor-β and suppressed T-cell proliferation in vitro. 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The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4+ T cells including regulatory T cells (Tregs) in CD45+ leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8+ T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8+ T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. 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subjects Analysis of Variance
Animals
CD8-Positive T-Lymphocytes - immunology
Cell Proliferation
Disease Models, Animal
gp100 Melanoma Antigen - immunology
gp100 Melanoma Antigen - metabolism
Humans
Immunology
Life Sciences
Lymphocyte Activation
Melanoma, Experimental - immunology
Melanoma, Experimental - pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Original
Random Allocation
Suppressor Factors, Immunologic - immunology
Suppressor Factors, Immunologic - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Tumor Cells, Cultured
title Impaired gp100-Specific CD8+ T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model
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