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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM10 Protein
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Adult
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Aged
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Cells, Cultured
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Coculture Techniques
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Female
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic
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Hodgkin Disease / genetics
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Hodgkin Disease / immunology
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Hodgkin Disease / metabolism*
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Humans
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Lymph Nodes / immunology
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Lymph Nodes / metabolism*
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Lymph Nodes / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mesenchymal Stem Cells / immunology
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology
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Middle Aged
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NK Cell Lectin-Like Receptor Subfamily K / genetics
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NK Cell Lectin-Like Receptor Subfamily K / metabolism*
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Protein Disulfide-Isomerases / genetics
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Protein Disulfide-Isomerases / metabolism*
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Receptors, Antigen, T-Cell, alpha-beta / metabolism
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Receptors, Antigen, T-Cell, gamma-delta / metabolism
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Reed-Sternberg Cells / immunology
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Reed-Sternberg Cells / metabolism
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Reed-Sternberg Cells / pathology
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
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Young Adult
Substances
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KLRK1 protein, human
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Antigen, T-Cell, gamma-delta
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Transforming Growth Factor beta
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human
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PDIA6 protein, human
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Protein Disulfide-Isomerases