Genome Biology (Apr 2021)

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

  • Shuang Qu,
  • Zichen Jiao,
  • Geng Lu,
  • Bing Yao,
  • Ting Wang,
  • Weiwei Rong,
  • Jiahan Xu,
  • Ting Fan,
  • Xinlei Sun,
  • Rong Yang,
  • Jun Wang,
  • Yongzhong Yao,
  • Guifang Xu,
  • Xin Yan,
  • Tao Wang,
  • Hongwei Liang,
  • Ke Zen

DOI
https://doi.org/10.1186/s13059-021-02331-0
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 24

Abstract

Read online

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.