TY - JOUR
T1 - High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas
AU - Zocchi, Maria Raffaella
AU - Catellani, Silvia
AU - Canevali, Paolo
AU - Tavella, Sara
AU - Garuti, Anna
AU - Villaggio, Barbara
AU - Zunino, Annalisa
AU - Gobbi, Marco
AU - Fraternali-Orcioni, Giulio
AU - Kunkl, Annalisa
AU - Ravetti, Jean Louis
AU - Boero, Silvia
AU - Musso, Alessandra
AU - Poggi, Alessandro
PY - 2012/2/9
Y1 - 2012/2/9
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-07-370841
DO - 10.1182/blood-2011-07-370841
M3 - Article
C2 - 22167753
AN - SCOPUS:84856836302
VL - 119
SP - 1479
EP - 1489
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -