Abstract
Previous studies have demonstrated that programmed death-1 ligand 1 (PD-L1) expressed in an aggressive activated B-cell (ABC)/non-germinal center B cell–like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL) is associated with inhibition of the tumor-associated T cell response. However, the molecular mechanism underlying PD-L1 expression in ABC-DLBCL remains unclear. Here, we report that MALT1 protease activity is required for ABC-DLBCL cells to evade cytotoxity of Vγ9Vδ2 T lymphocytes by generating substantial PD-L1+ ABC-DLBCL cells. While, NF-κB was dispensable for the PD-L1 expression induced by MALT1 protease activity in ABC-DLBCL cells. Furthermore, we showed that GLS1 expression was profoundly reduced by MALT1 protease activity inhibition, which resulted in insufficiency of glutaminolysis-derived mitochondrial bioenergetics. Activation of the PD-L1 transcription factor STAT3, which was strongly suppressed by glutaminolysis blockade, was rescued in a TCA (tricarboxylic acid) cycle-dependent manner by glutamate addition. Collectively, MALT1 protease activity coupled with glutaminolysis-derived mitochondrial bioenergetics plays an essential role in PD-L1 expression on ABC-DLBCL cells under immunosurveillance stress. Thus, our research sheds light on a mechanism underlying PD-L1 expression and highlights a potential therapeutic target to vanquish immune evasion by ABC-DLBCL cells.
Highlights
Diffuse large B-cell lymphoma (DLBCL) comprises the largest subgroup of non-Hodgkin lymphoma (NHL), accounting for ∼25% of all lymphoma cases [1]
activated B cell–like (ABC)-DLBCL cells showed fewer PI+ populations than germinal center B cell–like (GCB)-DLBCL cells when selected by Vγ9Vδ2 T lymphocytes at the various E/T ratios tested (Figure 1D), suggesting that ABCDLBCL cells were more inclined to subvert the cytotoxicity of Vγ9Vδ2 T lymphocytes
To further illustrate whether Mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) protease activity is involved in the tolerance of ABC-DLBCL cells to Vγ9Vδ2 T lymphocytes, we pretreated DLBCL cell lines with z-VRPR-fmk, a cell-permeable and irreversible MALT1 inhibitor. z-VRPR-fmk treatment efficiently blocked the proteolytic activity of MALT1, as indicated by the absence of the cleavedBCL10 fragment (Figure 1E)
Summary
Diffuse large B-cell lymphoma (DLBCL) comprises the largest subgroup of non-Hodgkin lymphoma (NHL), accounting for ∼25% of all lymphoma cases [1]. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is the first-line treatment for DLBCL patients and has contributed to an overall improvement in patient survival [4]. Many patients with DLBCL are unresponsive to the treatment and generally have a poor prognosis, patients with the ABC subtype [5, 6]. This may be related to the antiapoptotic effects of NF-κB that counteract the action of cytotoxic chemotherapy, since NF-κB activity is usually high in this tumor type [7]
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