PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity

Abstract

Background Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. Results Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. Conclusions In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

“…sPD-L1 can arise from a non-proteolytic process, via an alternative splicing. The PD-L1 gene (and corresponding PD-L1 pre-mRNA) can generate many different splice variants, including a long non-coding RNA isoform (PD-L1-lnc) [ 100 , 101 ] and a variety of variants leading to truncated proteins. These isoforms have been shown to play distinct roles in the regulation of immune surveillance and progression in colorectal cancer [ 102 , 103 ].…”

“…Different studies have indicated that sPD-L1 is a functional, glycosylated protein, capable of binding to PD-1 [ 127 ]. There are engineered variants of sPD-L1 (generated with directed molecular evolution) with an affinity over 20 folds greater than that of native human PD-L1 and able to compete with an anti-PD-1 antibody [ 101 ]. In this study, native human sPD-L1 was found to induce suppressive effects on activated T-cells, thus mimicking the effect of mPD-L1 [ 128 ].…”

SNX20AR/MiRNA-301a-3p/SNX20 Axis Associated With Cell Proliferation and Immune Infiltration in Lung Adenocarcinoma

“…LncRNA was reported that as an miRNA sponge to competitively binding miRNA and result in change the expression of downstream target genes. For example, the PDL1 related lncRNA was shown that through elevated the c-Myc expression and participate in the progression of lung adenocarcinoma (Qu et al, 2021). Chen et al (2020) found that LINC00173.v1 via inhibits the miR-511-5p to upregulation of VEGFA expression, result in boost the vascular endothelial cells growth and migration in lung squamous cell carcinoma.…”

The Emerging Roles of Long Noncoding RNAs as Hallmarks of Lung Cancer

“…Strategies employing gene silencing technology have been proposed to upregulate the tumor suppressive effects of lncRNAs, including Antisense oligonucleotides (ASOs), RNA interference (RNAi), and CRISPR/Cas9 (107). ASOs can attenuate the pro-tumor functions of lncRNA strands by directly binding to them and exhibit a synergistic anti-tumor effect in clinical studies when combined with RNAi technology (108), chemotherapeutic drugs (38), small molecule inhibitors (109), immune checkpoint antibodies (110), etc., which means lncRNA could be the appropriate targets for lung cancer treatment.…”