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

• Published in: bioRxiv
• Main Authors: Qu, Shuang, Jiao, Zichen, Lu, Geng, Yao, Bing, Wang, Ting, Rong, Weiwei, Xu, Jiahan, Fan, Ting, Sun, Xinlei, Yang, Rong, Wang, Jun, Yao, Yongzhong, Xu, Guifang, Yan, Xin, Wang, Tao, Liang, Hongwei, Zen, Ke
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 30.09.2020
• Subjects: Adenocarcinoma; Alternative splicing; Apoptosis; c-Myc protein; Cell proliferation; Immune response (cell-mediated); Immunotherapy; L1 protein; Lung cancer; Lymphocytes T; Metastases; Myc protein; Non-coding RNA; PD-L1 protein; Solid tumors; Transcription; γ-Interferon
• DOI: 10.1101/2020.09.29.282541

ABSTRACT Although blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ in a manner similar to PD-L1 mRNA. 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 directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc−c-Myc axis as a novel strategy for lung cancer therapy. Competing Interest Statement The authors have declared no competing interest.