Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy

Abstract

Immunotherapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting incompletely understood mechanisms of the immune checkpoint pathways. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interaction with components of endocytosis and nucleocytoplasmic transport pathways, which is regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune response-related genes and consequently enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune response gene expression, thereby advocating for targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

“…Here, we show that demethylation of ACE2 in the cytoplasmic tail is required for interaction with the importin-α complex and nuclear translocation. This is similar to recent findings showing that the immune checkpoint protein PD-L1, a major immunotherapy target, also translocates to the nucleus to control transcription in an importin-α-dependent manner via PTM regulation of its cytoplasmic tail through the non-histone role of epigenetic enzymes 77 . Furthermore, other important receptors such as EGFR also have nuclear functions mediated by PTMs catalyzed by epigenetic enzymes that allow nuclear translocation 78 .…”

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

“…However, a recent study revealed that nuclear PD-L1 has intrinsic functions that disrupt the effectiveness of anti-PD-1 immunotherapy. It demonstrated that PD-L1 nuclear translocation is controlled by acetylation and is associated with the efficacy of PD-1/PD-L1 targeted immunotherapy [ 60 ]. Furthermore, nuclear PD-L1 regulates several genes involved in immune responses, including NF-κB signal-related genes and major histocompatibility complex class I [ 59 , 60 , 61 ].…”

KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

“…Under hypoxia treatment, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation [ 41 ]. Another report found that deacetylation of PD-L1 at Lys 263 by HDAC2 triggers nuclear translocation by interacting with multiple proteins that are involved in endocytosis and nuclear import like HIP1R, vimentin [ 42 ]. Here in our study, we found that KPNB1 was the most relevant protein with PD-L1.…”

“…Recent new findings showed that nPD-L1 and p-Y705-Stat3 acted as co-activators in regulating GSDMC mRNA expression and then switched apoptosis to pyroptosis [ 41 ]. Moreover, nPD-L1 interacted with STAT3, c-Jun to govern immune-response-related genes expression and thereby modulated the anti-tumour immune response [ 42 ]. Sp1 is well identified as a common transcription factor that recognises the GC-rich DNA sequences in the promoter regions of various genes [ 46 , 47 ].…”