title: Heat shock protein 90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4(+) T cells.
abstract: Tumor Ag-specific CD4(+) T cells play important functions in tumor immunosurveillance, and in certain cases they can directly recognize HLA class II-expressing tumor cells. However, the underlying mechanism of intracellular Ag presentation to CD4(+) T cells by tumor cells has not yet been well characterized. We analyzed two naturally occurring human CD4(+) T cell lines specific for different peptides from cytosolic tumor Ag NY-ESO-1. Whereas both lines had the same HLA restriction and a similar ability to recognize exogenous NY-ESO-1 protein, only one CD4(+) T cell line recognized NY-ESO-1(+) HLA class II-expressing melanoma cells. Modulation of Ag processing in melanoma cells using specific molecular inhibitors and small interfering RNA revealed a previously undescribed peptide-selective Ag-presentation pathway by HLA class II(+) melanoma cells. The presentation required both proteasome and endosomal protease-dependent processing mechanisms, as well as cytosolic heat shock protein 90-mediated chaperoning. Such tumor-specific pathway of endogenous HLA class II Ag presentation is expected to play an important role in immunosurveillance or immunosuppression mediated by various subsets of CD4(+) T cells at the tumor local site. Furthermore, targeted activation of tumor-recognizing CD4(+) T cells by vaccination or adoptive transfer could be a suitable strategy for enhancing the efficacy of tumor immunotherapy.
authors.affiliation: Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018841:HSP90 Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex