Overexpression of GLT1D1 induces immunosuppression through glycosylation of PD-L1 and predicts poor prognosis in B-cell lymphoma.

B-cell non-Hodgkin's lymphoma (NHL) is a class of heterogeneous diseases with variable clinical outcomes. Immunosuppression is particularly common in the subtypes of lymphoma with poor prognosis, but the underlying mechanism remains unclear. Using a RT-PCR array analysis, we have identified that glycosyltransferase 1 domain-containing 1 (GLT1D1), an enzyme that transfers glycosyl groups to proteins, is highly upregulated in the incurable subtype of B-cell NHL and in early relapse diffuse large B-cell lymphoma. Analysis of clinical specimens revealed that GLT1D1 expression was positively correlated with the level of glycosylated programmed cell death-ligand 1 (PD-L1) in B-cell NHL and that high GLT1D1 expression was associated with poor prognosis. Mechanistically, we showed that GLT1D1 transferred N-linked glycans to PD-L1, thus promoting the immunosuppressive function of glycosylated PD-L1. Downregulation of GLT1D1 resulted in a decrease of glycosylated PD-L1 and enhanced cytotoxic T-cell function against lymphoma cells. In vivo, overexpression of GLT1D1 promoted tumor growth by facilitating tumor immune escape through increased levels of PD-L1. Our work has identified GLT1D1 as a predictive biomarker for B-cell NHL. It has also shown that this enzyme enhances PD-L1 stabilization via N-glycosylation, thus promoting immunosuppression and tumor growth. As such, GLT1D1 might be a novel therapeutic target for the treatment of B-NHL.