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  3. A translational study on the survival and molecular mechanism of PD-L1 expression in EGFR-mutant NSCLC treated with osimertinib

A translational study on the survival and molecular mechanism of PD-L1 expression in EGFR-mutant NSCLC treated with osimertinib

  • iScience. 2025 Nov 21;28(12):114175. doi: 10.1016/j.isci.2025.114175.
Shidong Xu 1 2 3,  Yangqian Chen 3,  Xing Zhang 3,  Xuexue Zhou 3,  Jiacheng Dai 3,  Yuanze Sun 3,  Jie Zou 2,  Yahui Chen 2,  Linrui Ma 3,  Zhe Huang 3,  Liang Zeng 3 4,  Yongchang Zhang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Pathology and Pathophysiology, School of Basic Medical Science, Central South University, Changsha 410078, China.
  • 2 Department of Immunology, School of Basic Medical Science, Central South University, Changsha 410078, China.
  • 3 Department of Medical Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
  • 4 Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
PMID: 41446744 DOI: 10.1016/j.isci.2025.114175
Abstract

Highly expressed programmed death-ligand 1 (PD-L1) has been associated with poor clinical outcomes in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung Cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). However, the prognostic significance of PD-L1 expression in the context of first-line osimertinib treatment remains unclear. In this retrospective study, we analyzed 317 patients with EGFR-mutated stage III-IV lung adenocarcinoma treated with first-line osimertinib. Patients with high PD-L1 expression demonstrated significantly shorter progression-free survival and overall survival compared to those with low PD-L1 expression. Transcriptomic analysis revealed upregulation of interferon-gamma (IFN-γ) and interleukin (IL)-6/JAK/STAT3 pathways in high PD-L1 tumors. Flow cytometry identified an increased proportion of CD56bright natural killer (NK) cells in patients with high PD-L1 expression. In vitro experiments further demonstrated that IFN-γ induces PD-L1 expression via STAT3 activation. These findings provide evidence that baseline PD-L1 expression may serve as a prognostic biomarker for patients with EGFR-mutated NSCLC receiving first-line osimertinib and implicate the CD56bright NK cell/IFN-γ/STAT3 axis in the regulation of PD-L1 expression.

Keywords

Oncology; Therapeutics.

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