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Purpose <p>High programmed death-ligand 1 (PD-L1) expression is associated with unfavorable clinical outcomes in epidermal growth factor receptor (<i>EGFR)</i>-mutated lung adenocarcinomas (LUAD) patients treated with tyrosine kinase inhibitors (TKIs) or anti-PD-1/PD-L1 therapy, yet the underlying mechanisms are less explored.</p> Methods <p>Bulk RNA sequencing (RNA-seq) datasets were analyzed to investigate intertumoral transcriptional variations linked to PD-L1 expression. Immunohistochemistry (IHC) was utilized to quantify PD-L1 expression on tumor cells. Digital spatial profiling (DSP) was performed on 23 <i>EGFR</i>-mutated LUAD tissue samples to characterize transcriptomic differences in tumor cell (TC), immune cell (IM), and macrophage (MA) compartments between PD-L1 high and low groups. Furthermore, a publicly available DSP dataset was analyzed and IHC was conducted for validation.</p> Results <p>Analysis of RNA-seq datasets identified differentially expressed genes, signaling pathways, and immune profiles associated with PD-L1 expression. Compared to low PD-L1 tumors, high PD-L1 tumors exhibited increased infiltration of T regulatory cells (Tregs) and enhanced immunosuppressive signatures. DSP analysis revealed compartment-specific molecular disparities: TC segment in high PD-L1 tumors showed upregulated signatures of cell proliferation, invasion, and metastasis. IM segment displayed increased infiltration of immunosuppressive cells, including Tregs and myeloid-derived suppressor cells and upregulated expression of inhibitory immunomodulators <i>CD276</i>, <i>HAVCR2</i>, and <i>LGALS9C</i>.</p> Conclusion <p>Combining bulk and spatial RNA-seq, this study characterized the molecular and immunological hallmarks of <i>EGFR</i>-mutated LUAD in the context of PD-L1 expression, providing new insights into the development of tailored therapeutic strategies for <i>EGFR</i>-mutated LUAD with high PD-L1 expression.</p>

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Spatially resolved whole-transcriptomic profiling of EGFR-mutated lung adenocarcinomas stratified by PD-L1 expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Chenxi Yu,
  • Chenxi Shi,
  • Hao Zhou,
  • Na Li,
  • Ruyi Ma,
  • SongBai Liu,
  • Zaixiang Tang,
  • Xianling Zhang,
  • Zhe Lei,
  • Hualong Qin

摘要

Purpose

High programmed death-ligand 1 (PD-L1) expression is associated with unfavorable clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas (LUAD) patients treated with tyrosine kinase inhibitors (TKIs) or anti-PD-1/PD-L1 therapy, yet the underlying mechanisms are less explored.

Methods

Bulk RNA sequencing (RNA-seq) datasets were analyzed to investigate intertumoral transcriptional variations linked to PD-L1 expression. Immunohistochemistry (IHC) was utilized to quantify PD-L1 expression on tumor cells. Digital spatial profiling (DSP) was performed on 23 EGFR-mutated LUAD tissue samples to characterize transcriptomic differences in tumor cell (TC), immune cell (IM), and macrophage (MA) compartments between PD-L1 high and low groups. Furthermore, a publicly available DSP dataset was analyzed and IHC was conducted for validation.

Results

Analysis of RNA-seq datasets identified differentially expressed genes, signaling pathways, and immune profiles associated with PD-L1 expression. Compared to low PD-L1 tumors, high PD-L1 tumors exhibited increased infiltration of T regulatory cells (Tregs) and enhanced immunosuppressive signatures. DSP analysis revealed compartment-specific molecular disparities: TC segment in high PD-L1 tumors showed upregulated signatures of cell proliferation, invasion, and metastasis. IM segment displayed increased infiltration of immunosuppressive cells, including Tregs and myeloid-derived suppressor cells and upregulated expression of inhibitory immunomodulators CD276, HAVCR2, and LGALS9C.

Conclusion

Combining bulk and spatial RNA-seq, this study characterized the molecular and immunological hallmarks of EGFR-mutated LUAD in the context of PD-L1 expression, providing new insights into the development of tailored therapeutic strategies for EGFR-mutated LUAD with high PD-L1 expression.