Portal de Periódicos da CAPES

High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas

2011; Elsevier BV; Volume: 119; Issue: 6 Linguagem: Inglês

10.1182/blood-2011-07-370841

1528-0020

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,

CAR-T cell therapy research

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.