title: High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas.
abstract: Herein we describe that in classic Hodgkin lymphomas (cHL, n = 25) the lymph node (LN) stroma displayed in situ high levels of transcription and expression of the disulfide-isomerase ERp5 and of the disintegrin-metalloproteinase ADAM10, able to shed the ligands for NKG2D (NKG2D-L) from the cell membrane. These enzymes were detected both in LN mesenchymal stromal cells (MSCs) and in Reed-Sternberg (RS) cells; in addition, MIC-A and ULBP3 were present in culture supernatants of LN MSCs or RS cells. NKG2D-L-negative RS cells could not be killed by CD8(+)αβT or γδT cells; tumor cell killing was partially restored by treating RS cells with valproic acid, which enhanced NKG2D-L surface expression. Upon coculture with LN MSCs, CD8(+)αβT and γδT cells strongly reduced their cytolytic activity against NKG2D-L(+) targets; this seems to be the result of TGF-β, present at the tumor site, produced in vitro by LN MSCs and able to down-regulate the expression of NKG2D on T lymphocytes. In addition, CD8(+)αβT and γδT cells from the lymph nodes of cHL patients, cocultured in vitro with LN MSCs, underwent TGF-β-mediated down regulation of NKG2D. Thus, in cHL the tumor microenvironment is prone to inhibit the development of an efficient antitumor response.
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy. zocchi.maria@hsr.it
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.forename: Silvia
authors.initials: S
authors.lastname: Catellani
authors.forename: Paolo
authors.initials: P
authors.lastname: Canevali
authors.forename: Sara
authors.initials: S
authors.lastname: Tavella
authors.forename: Anna
authors.initials: A
authors.lastname: Garuti
authors.forename: Barbara
authors.initials: B
authors.lastname: Villaggio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zunino
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Giulio
authors.initials: G
authors.lastname: Fraternali-Orcioni
authors.forename: Annalisa
authors.initials: A
authors.lastname: Kunkl
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Ravetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Boero
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musso
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: C527085:KLRK1 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016212:Transforming Growth Factor beta; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases