BTK inhibitors upregulate NKG2D ligand expression by modulating IL-10/STAT3 in activated non-GCB diffuse large B-cell lymphoma cells

Abstract

Abstract This study aimed to investigate the role of the IL-10/STAT3 pathway in BTK inhibitor-induced NKG2D ligand (MICA and ULBP2) expression in non-GCB DLBCL cells. The expression of NKG2D ligands and IL-10/STAT3 in SUDHL4, U2932 and OCI-LY3 cells was detected by western blotting. After stimulation of the BCR signalling pathway with IgM antibodies, NKG2D ligand expression levels were significantly reduced, as were IL-10 and p-STAT3 levels. Ibrutinib treatment produced the opposite effects of IgM antibody treatment. Treatment of U2932 and OCI-LY3 cells with a STAT3 inhibitor (STAT3-IN-1) upregulated NKG2D ligand expression and downregulated IL-10 expression. When IL-10 neutralizing antibodies were added, p-STAT3 expression levels decreased, while NKG2D ligand expression levels increased. Similar results to those of ibrutinib were obtained when the BTK inhibitors ACP-196 and BGB-3111 were added. Our findings indicate that the IL-10/STAT3 pathway is involved in the upregulation of NKG2D ligands induced by BTK inhibitors in U2932 and OCI-LY3 cells.