PD-L1 lncRNA splice promotes lung adenocarcinoma proliferation and metastasis via enhancing c-Myc activity

Abstract

Abstract Although blockade of programmed death-ligand 1 (PD-L1) to suppress T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is low for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that, via alternative splicing, human PD-L1 protein positive or negative lung adenocarcinoma all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc), which promotes lung adenocarcinoma proliferation and metastasis. Analyses of various lung adenocarcinoma cells show that PD-L1-lnc is significantly upregulated by IFNg in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and metastasis, but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc signaling downstream in lung adenocarcinoma cells. Therefore, targeting PD-L1-lnc/c-Myc axis provides a novel strategy for lung cancer therapy.