A prospective multi-cohort study identifies and validates a 5-gene peripheral blood signature predictive of immunotherapy response in non-small cell lung cancer

Mol Cancer. 2024 Nov 6;23(1):247. doi: 10.1186/s12943-024-02160-2.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC.

Methods: We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS).

Results: In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80-0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07-0.58, p = 0.005).

Conclusion: Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.

Keywords: Blood-based; Clinical utility; ICIs; NSCLC; Predictive biomarkers.

Publication types

  • Letter

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor* / genetics
  • Carcinoma, Non-Small-Cell Lung* / blood
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / mortality
  • Cohort Studies
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy / methods
  • Lung Neoplasms* / blood
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / mortality
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • Transcriptome
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors