title: A key role of GARP in the immune suppressive tumor microenvironment.
abstract: In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-β dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype. Notably, proliferation of cytotoxic T cells and their effector function is inhibited in the presence of sGARP. GARP expression on Treg and melanoma cells is significantly decreased in the presence of agents such as IFN-α, thus explaining at least in part a novel mechanism of action of this adjuvant therapy.In conclusion, GARP in its soluble and membrane bound form contributes to peripheral tolerance in a multipronged way, potentiates the immunosuppressive tumor microenvironment and thus acts as a negative regulator in melanoma patients. Therefore, it may qualify as a promising target and a new checkpoint for cancer immunotherapy.
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Neuhoff
authors.affiliation: Department of Dermatology, University Medical Center, Bonn, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schupp
authors.affiliation: Department of Medicine II, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Eberts
authors.affiliation: Institute of Neuropathology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Leukel
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weilbaecher
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University, Mainz, Germany.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.affiliation: Department of Dermatology, University Medical Center, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tueting
authors.affiliation: Department of Medicine II, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lennerz
authors.affiliation: Institute of Neuropathology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tuettenberg
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D007371:Interferon-gamma
keywords: GARP; Treg; melanoma; tolerance; tumor microenvironment