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Background <p>Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), yet their use is associated with a notable risk of immune-related adverse events, including checkpoint inhibitor–associated pneumonitis (CIP). The real-world incidence, risk magnitude, and underlying immunopathogenesis of CIP in NSCLC remain inadequately defined.</p> Methods <p>We conducted a retrospective cohort study using electronic health records from 21,671 NSCLC patients, categorized into ICI (<i>n</i> = 8,744) and non-ICI (<i>n</i> = 12,927) groups. Incidence of pneumonitis was evaluated using propensity score–matched analysis, Kaplan-Meier curves, and Cox regression models. Subgroup analyses were performed across demographic and clinical variables. Differentially expressed genes (DEGs) from transcriptomic datasets were analyzed to explore inflammatory mechanisms, including GO/KEGG pathway enrichment, protein–protein interaction (PPI) network construction, and single-sample gene set enrichment analysis (ssGSEA).</p> Results <p>The incidence of pneumonitis was significantly higher in the ICI group (28.9%) compared to the non-ICI group (10.0%) (hazard ratio [HR] = 2.86; 95% confidence interval [CI], 2.43–3.29; <i>P</i> &lt; 0.001). This elevated risk persisted across age, sex, BMI, comorbidities, and autoimmune status. Transcriptomic analysis revealed distinct upregulation of immune-related genes (e.g., TCF7L1, ATP1B4, RPL18A), with enrichment of pathways including IFN-γ signaling, Th17 differentiation, TNF and JAK-STAT signaling. ssGSEA confirmed increased immune activation scores in CIP samples. PPI network and hub gene analysis identified GHRH, ZBTB21, and PLAU as central regulators.</p> Conclusions <p>ICI use in NSCLC is associated with a markedly increased risk of pneumonitis. Transcriptomic profiling suggests that overactivation of pro-inflammatory immune pathways underlies CIP pathogenesis.</p>

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Checkpoint inhibitor–associated pneumonitis in non-small cell lung cancer: a cohort study with transcriptomic analysis of inflammatory mechanisms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Wenbo Zhao,
  • Shiju Shen,
  • Huafang Zhao

摘要

Background

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), yet their use is associated with a notable risk of immune-related adverse events, including checkpoint inhibitor–associated pneumonitis (CIP). The real-world incidence, risk magnitude, and underlying immunopathogenesis of CIP in NSCLC remain inadequately defined.

Methods

We conducted a retrospective cohort study using electronic health records from 21,671 NSCLC patients, categorized into ICI (n = 8,744) and non-ICI (n = 12,927) groups. Incidence of pneumonitis was evaluated using propensity score–matched analysis, Kaplan-Meier curves, and Cox regression models. Subgroup analyses were performed across demographic and clinical variables. Differentially expressed genes (DEGs) from transcriptomic datasets were analyzed to explore inflammatory mechanisms, including GO/KEGG pathway enrichment, protein–protein interaction (PPI) network construction, and single-sample gene set enrichment analysis (ssGSEA).

Results

The incidence of pneumonitis was significantly higher in the ICI group (28.9%) compared to the non-ICI group (10.0%) (hazard ratio [HR] = 2.86; 95% confidence interval [CI], 2.43–3.29; P < 0.001). This elevated risk persisted across age, sex, BMI, comorbidities, and autoimmune status. Transcriptomic analysis revealed distinct upregulation of immune-related genes (e.g., TCF7L1, ATP1B4, RPL18A), with enrichment of pathways including IFN-γ signaling, Th17 differentiation, TNF and JAK-STAT signaling. ssGSEA confirmed increased immune activation scores in CIP samples. PPI network and hub gene analysis identified GHRH, ZBTB21, and PLAU as central regulators.

Conclusions

ICI use in NSCLC is associated with a markedly increased risk of pneumonitis. Transcriptomic profiling suggests that overactivation of pro-inflammatory immune pathways underlies CIP pathogenesis.