Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1

Abstract

PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells. To this effect contributed the increased transcription, in correlation with histone acetylation of the PD-L1 gene and the acetylation of PD-L1 protein, which led to an increased interaction with TRAPPC4, molecule involved in PD-L1 recycling to the cell membrane. Interestingly, the BRD4 inhibitor JQ-1, counteracted PD-L1 transcription and reduced its surface expression, suggesting that such a combination could improve the outcome of VPA treatment, also because it increased the cytotoxic effect of VPA. Also considering that this HDACi did not upregulate PD-L2 and that the supernatant of VPA-treated cancer cells did not increase PD-L1 expression on the surface of macrophages exposed to it.

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

“…Nuclear PD-L1 also upregulates other immune checkpoint genes and angiogenesis markers in breast cancer. EGF enhances PD-L1 acetylation [ 33 ], while VPA increases PD-L1 recycling to the membrane, highlighting complex regulatory mechanisms [ 127 ]. (Fig.…”

“…HDAC2 inhibitors combined with PD-1 antibodies have been shown to significantly delay tumor growth and improve survival in syngeneic MC38 mouse models [ 22 ]. JQ-1, which reduces PD-L1 expression through acetylation, shows potential for treating pancreatic cancer [ 127 ]. Pevonedistat, a NEDDylation inhibitor, is undergoing clinical trials for various cancers and may upregulate PD-L1 expression, although its effectiveness is still under study [ 203 , 204 ].…”