title: Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity.
abstract: In the absence of a local inflammatory response, expression of MHC class II molecules is restricted mainly to hematopoietic cells and thymus epithelium. However, certain tumors, such as melanoma, may acquire aberrant constitutive expression of MHC class II. In a set of primary melanoma cell populations and correspondingly expanded autologous tumor-infiltrating lymphocytes (TIL), we show how MHC class II expression on melanoma cells associates with strong MHC class II-restricted CD4(+) T-cell responses that are specific for tumors. Notably, we found that tumor-specific CD4(+) T-cell responses were dominated by TNF production. TNF reduced CD8(+) T-cell activation in IFNγ-rich environments resembling a tumor site. Conversely, direct CD4(+) T-cell responses had no influence on either the proliferation or viability of melanoma cells. Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. Department of Biomedical Sciences, University of Catania, Catania, Italy. inge.marie.svane@regionh.dk marco.donia@regionh.dk.
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Andersen
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Kjeldsen
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Shamaila
authors.initials: S
authors.lastname: Munir
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Thor Straten
authors.affiliation: Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark. inge.marie.svane@regionh.dk marco.donia@regionh.dk.
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D059425:Interferon-gamma Release Tests; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D006681:HLA-D Antigens