title: MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis.
abstract: Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3-MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.
authors: INSERM Unité Mixte de Recherche Scientifique 976, Université Paris-Diderot Paris 7, Hôpital Saint-Louis Assistance Publique des Hôpitaux de Paris, 75010 Paris, France.
authors: Patrice
authors: P
authors: Hemon
authors: Francette
authors: F
authors: Jean-Louis
authors: Kiran
authors: K
authors: Ramgolam
authors: Chrystelle
authors: C
authors: Brignone
authors: Manuelle
authors: M
authors: Viguier
authors: Hervé
authors: H
authors: Bachelez
authors: Frédéric
authors: F
authors: Triebel
authors: Dominique
authors: D
authors: Charron
authors: Fawzi
authors: F
authors: Aoudjit
authors: Reem
authors: R
authors: Al-Daccak
authors: Laurence
authors: L
authors: Michel
mesh_terms: D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human