title: Impaired gp100-Specific CD8(+) T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model.
abstract: 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.
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: David G
authors.initials: DG
authors.lastname: Mairhofer
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ortner
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria; Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria.
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Tripp
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria; Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schaffenrath
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria; Department of Dermatology, Laboratory of DC-Biology, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Fleming
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria; Department of Dermatology, Laboratory of DC-Biology, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Heger
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Komenda
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria; Oncotyrol, Center for Personalized Cancer Medicine, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Reider
authors.affiliation: Department of Dermatology, Laboratory of DC-Biology, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Dudziak
authors.affiliation: Department of Chemical Biology, Lab for Cancer Research, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department for Translational Dermato-Oncology, Center for Medical Biotechnology, University Hospital Essen, Essen, Germany.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Vincent
authors.initials: V
authors.lastname: Flacher
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: patrizia.stoitzner@i-med.ac.at.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011897:Random Allocation; D013491:Suppressor Factors, Immunologic / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D058951:gp100 Melanoma Antigen / Q000276:immunology* / Q000378:metabolism
chemical_list: D013491:Suppressor Factors, Immunologic; D058951:gp100 Melanoma Antigen