The Potential Impact of BI-D1870, a Ribosomal S6 Kinase Inhibitor, on PD-L1 Expression Control

Abstract

The immune checkpoint blockade is a promising strategy for cancer immunotherapy. Expression of programmed death protein ligand 1 (PD-L1) is often upregulated in tumors with high genomic instability. Cytoplasmic DNA results from genomic instability and stimulates the transcription of type I interferon (IFN) via the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway. Type I IFN stimulates the JAK-STAT pathway, leading to the transcription of IFN-stimulated genes and PD-L1. Hence, the cGAS-STING pathway is a potential therapeutic target. However, its precise regulatory mechanism remains elusive. Here, we showed that BI-D1870, an inhibitor of ribosomal S6 kinases (RSKs), attenuated PD-L1 transcription by inhibiting TBK1 activation in cGAS-STING signaling triggered by cytoplasmic DNA. BI-D1870 strongly downregulated PD-L1; therefore, it could be a potential therapeutic drug for impaired tumor immune escape.