title: Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells.
abstract: The 90-kDa heat shock protein (Hsp90) has become an important therapeutic target with ongoing evaluation in a number of malignancies. Although Hsp90 inhibitors have a high therapeutic index with limited effects on normal cells, they have been described to inhibit dendritic cell function. However, its effect on human immune effector cells may have significant clinical implications, but remains unexplored. In this study, we have evaluated the effects of Hsp90 inhibition on human T lymphocyte and NK cells, including their Ag expression, activation, proliferation, and functional activities. These studies demonstrate that Hsp90 inhibition irreversibly downregulates cell surface expression of critical Ags (CD3, CD4, CD8), the costimulatory molecule (CD28, CD40L), and αβ receptors on T lymphocytes, as well as activating receptors (CD2, CD11a, CD94, NKp30, NKp44, NKp46, KARp50.3) on NK cells. Hsp90 inhibition significantly reduced CD4 protein expression on T lymphocytes at both the cell surface and intracellular level, which was shown to be associated with aberrant regulation of Src-kinase p56(Lck). Downregulation of the Ags triggered by Hsp90 inhibition on CD3(+) T lymphocytes, both in CD4(+) and CD8(+) T cell subsets, was associated with a disruption in their cellular activation, proliferation, and/or IFN-γ production, when the inhibition occurred either in activated or inactivated cells. In addition, downregulation of key activating receptors on NK cells following Hsp90 inhibition resulted in decreased cytotoxicity against tumor cells. Therefore, these observations demonstrate the need to closely monitor immune function in patients being treated with a Hsp90 inhibitor and may provide a potential therapeutic application in autoimmune diseases.
authors.affiliation: Department of Medical Oncology, The Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jooeun
authors.initials: J
authors.lastname: Bae
authors.forename: Aditya
authors.initials: A
authors.lastname: Munshi
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Mehmet
authors.initials: M
authors.lastname: Samur
authors.forename: Rao
authors.initials: R
authors.lastname: Prabhala
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016227:Benzoquinones; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C001277:geldanamycin