Epithelial−mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer

• Published in: British journal of cancer Vol. 131; no. 1; pp. 23 - 36
• Main Authors: Jeong, Hyein, Koh, Jaemoon, Kim, Sehui, Song, Seung Geun, Lee, Soo Hyun, Jeon, Youngjoo, Lee, Chul-Hwan, Keam, Bhumsuk, Lee, Se-Hoon, Chung, Doo Hyun, Jeon, Yoon Kyung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2024; Nature Publishing Group
• Subjects: 631/67/327; 692/4028/67/1059/2325; 692/4028/67/1612/1350; 692/53/2423; Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cytotoxicity; Drug Resistance; Epidemiology; Epithelial-Mesenchymal Transition; Female; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Infiltration; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes T; Macrophages; MAP kinase; Metastases; Mice; Mice, Nude; Molecular Medicine; Non-small cell lung carcinoma; Oncology; PD-L1 protein; Phenotypes; Protein phosphatase; Signal Transduction; Small cell lung carcinoma; Transforming Growth Factor beta - metabolism; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02698-4

Background We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial−mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. Methods PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. Results RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-β (TGFβ). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFβ production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. Conclusions Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.