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

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

Shaoqiu Chen #  1   2 , Fangfang Liu #  3 , Yuanyuan Fu  1 , Chris K Deng  1 , Jeffrey A Borgia  4 , Abdul-Ghani Ayman  5 , Masaki Nasu  1 , Mayumi Jijiwa  1 , Hua Yang  1 , Ting Gong  1   2 , Junlong Wang  1   2 , Zhougui Ling  6 , Xiaoyan Wang  7 , Hongwei Wang  8 , Qian Chu  9 , Youping Deng  10
Affiliations

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

Shaoqiu Chen et al. Mol Cancer. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Transcriptomic Analysis Outcomes. A: Meta-score distribution of the 5-gene signature inresponders and non-responders of the PMBCR (WHTJ) training cohort. B: Meta-score distribution of the 5-genesignature in responders and non-responders of the BC(RUMC)validation cohort. C Meta-score distribution of the 5-gene signature in responders and non-responders of the PBMCP (WHTJ) prospective validation cohort. D: ROCcurve analysis demonstrating the predictive performance of the 5-gene signature in the PMBCR cohort (AUC=0.90,95% CI: 0.82-0.99). E: ROC curve analysis confirming the predictive value of the 5-gene signature in the BC(RUMC) validation cohort (AUC=0.89, 95% CI: 0.75-1.00). F: ROC curve analysis validating the predictive accuracyof the 5-gene signature in the prospective PBMCP cohort (AUC=0.89, 95% CI: 0.80-0.99)
Fig. 2
Fig. 2
Survival Analysis Demonstrating the Prognostic Value of the 5-Gene Signature. A: Kaplan-Meiercurves for progression-free survival (PFS) in the PMBCR cohort, revealing a significant survival benefit for patientspredicted as responders by the 5-gene signature compared to predicted non-responders (P < 0.001). B: Kaplan-Meier curves for PFS in the prospective PBMCP cohort, confirming the prognostic value of the 5-gene signature,with predicted responders exhibiting significantly longer PFS than predicted non-responders (P < 0.001). C: Kaplan-Meier curves for PFS in the BC cohort, demonstrating a significant survival advantage for predicted respondersover predicted non-responders based on the 5-gene signature (P < 0.001). D: Kaplan-Meier curves for overallsurvival (OS) in the BC cohort, showing a significant survival benefit for patients predicted as responders by the 5-gene signature compared to predicted non-responders (P < 0.001)
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