Original Research ARTICLE
Glutaminolysis mediated by MALT1 protease activity facilitates PD-L1 expression on ABC-DLBCL cells and contributes to their immune evasion
- 1Jinan University, China
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.
Keywords: Diffuse large B-cell lymphoma, MALT1 protease activity, Glutaminolysis, PD-L1, Immune Evasion
Received: 27 Sep 2018;
Accepted: 04 Dec 2018.
Edited by:Boris Zhivotovsky, Karolinska Institute (KI), Sweden
Reviewed by:Denise P. Carvalho, Universidade Federal do Rio de Janeiro, Brazil
Catherine Brenner, PhD, INSERM U1180 Signalisation et Physiopathologie Cardiovasculaire, France
Copyright: © 2018 Xia, Zhou, Guo, Fu, Li, Xu, Zheng, Zhang, Shan and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Yunfei Gao, Jinan University, Guangzhou, 510632, Guangdong Province, China, email@example.com