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: Maria Raffaella Zocchi, Silvia Catellani, Paolo Canevali, Sara Tavella, Anna Garuti, Barbara Villaggio, Annalisa Zunino, Marco Gobbi, Giulio Fraternali-Orcioni, Annalisa Kunkl, Jean-Louis Ravetti, Silvia Boero, Alessandra Musso, Alessandro Poggi
• Journal: Blood (Blood) Vol. 119 Issue 6 Pg. 1479-89 (Feb 09 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22167753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KLRK1 protein, human
• Membrane Proteins
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Antigen, T-Cell, gamma-delta
• Transforming Growth Factor beta
• Amyloid Precursor Protein Secretases
• ADAM Proteins
• ADAM10 Protein
• ADAM10 protein, human
• PDIA6 protein, human
• Protein Disulfide-Isomerases

Topics

• ADAM Proteins (genetics, metabolism)
• ADAM10 Protein
• Adult
• Aged
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Cells, Cultured
• Coculture Techniques
• Female
• Fluorescent Antibody Technique
• Gene Expression Regulation, Neoplastic
• Hodgkin Disease (genetics, immunology, metabolism)
• Humans
• Lymph Nodes (immunology, metabolism, pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mesenchymal Stem Cells (immunology, metabolism, pathology)
• Middle Aged
• NK Cell Lectin-Like Receptor Subfamily K (genetics, metabolism)
• Protein Disulfide-Isomerases (genetics, metabolism)
• Receptors, Antigen, T-Cell, alpha-beta (metabolism)
• Receptors, Antigen, T-Cell, gamma-delta (metabolism)
• Reed-Sternberg Cells (immunology, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (immunology, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Tumor Microenvironment (genetics, immunology)
• Young Adult