Glutaminolysis Mediated by MALT1 Protease Activity Facilitates PD-L1 Expression on ABC-DLBCL Cells and Contributes to Their Immune Evasion

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.

Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC‐DLBCL cells

“…Recently, new evidence points to a more intimate link between mitochondrial bioenergetics and apoptosis, mediated by the remodeling of the mitochondrial ultrastructure during apoptosis . Our previous study reported that mitochondrial bioenergetics were attenuated by short‐term inhibition of MALT1 protease in ABC‐DLBCL cells . This inhibitory effect was also preserved even with prolonged MALT1 protease inhibition, revealing that irreversible destruction of mitochondrial bioenergetics is caused by MALT1 protease inhibition.…”

“…However, both ATP production and mitochondrial mass also declined. Despite this, mitochondrial mass was not impaired by short‐term MALT1 protease inhibition, which implied the decreased mitochondrial mass might be caused by other intermediate factors associated with MALT1 protease. Excess mitochondrial ROS oxidizes biomolecules, including lipids, proteins, and nucleic acids, leading to damage and malfunction of mitochondria .…”

“…35 Our previous study reported that mitochondrial bioenergetics were attenuated by short-term inhibition of MALT1 protease in ABC-DLBCL cells. 29 This inhibitory effect was also preserved even with prolonged MALT1 protease inhibition, revealing that irreversible destruction of mitochondrial bioenergetics is caused by MALT1 protease inhibition. However, both ATP production and mitochondrial mass also declined.…”

“…These research results suggest that controlling mitochondrial redox homeostasis is essential for ABC‐DLBCL to resist apoptosis. Our previous study found that MALT1 protease facilitated the glutaminolysis pathway in ABC‐DLBCL cells . Glutamate derived from glutaminolysis could be metabolized into other molecules, such as GSH and nicotinamide adenine dinucleotide phosphate (NADPH), which protect cancerous cells from oxidative stress .…”

“…Our previous study found that MALT1 protease facilitated the glutaminolysis pathway in ABC-DLBCL cells. 29 Glutamate derived from glutaminolysis could be metabolized into other molecules, such as GSH and nicotinamide adenine dinucleotide phosphate (NADPH), which protect cancerous cells from oxidative stress. 30 Thus, we believe that MALT1 protease is probably involved in regulating mitochondrial redox homeostasis.…”