MTSS1 Curtails Lung Adenocarcinoma Immune Evasion by Promoting AIP4-Mediated PD-L1 Monoubiquitination and Lysosomal Degradation

MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation

PD-L1/PD-1 immune therapy for the treatment of cancer has shown tremendous promise; however, there are growing examples of poor response and drug resistance.  Many studies have been performed to better understand how PD-L1 is regulated at the genetic, transcription, and translational levels.  Recent data by Wang et al. identified a mechanism by which monoubiquitination of PD-L1 via MTSS1/AIP4 dependent mechanisms is critical for PD-L1 expression and lung adenocarcinoma immune evasion.  Utilizing immune-compromised mouse models, the group showed that MTSS1 suppressed lung adenocarcinoma progression in a host-immunity-dependent fashion.  They then identified PD-L1 changes as a critical mechanism by which MTSS1 regulated host immunity.  Utilizing MTSS1 knockdown and overexpression in cultured cells, they effectively measured its effect on PD-L1 expression.  Control of PD-L1 expression occurred at the protein level through the regulation of lysosomal degradation.  This led them to investigate whether MTSS1 controlled the ubiquitination state of PD-L1 and identified monoubiquitination of PD-L1 at lysine 263 as an essential modification.  Importantly, AIP4 was identified as the critical E3 ubiquitin ligase that is recruited by MTSS1.  Additional studies showed that EGFR/Ras signaling could alter MTSS1 levels to control PD-L1 and immune surveillance.  Finally, the group utilized combinatorial drugs to enhance immune checkpoint blockade, which suppressed lung adenocarcinoma progression in immune-compromised mouse models.  Cytoskeleton Inc’s studies on PD-L1 ubiquitination using the Signal-Seeker™ Ubiquitination Detection Kit (Cat. # BK161) played a critical role in identifying this critical post-translational modification of a key, immune checkpoint protein.