What question did this study set out to answer?

The study aims to evaluate the relationship between dual biomarkers PD-L1 on circulating tumor cells and PD-1 on CD8+ T cells with immunotherapy outcomes in advanced non-small cell lung cancer.

March 21, 2026Open Access

Circulating Tumor Cell PD-L1 and Peripheral Blood CD8+ T-Cell PD-1 as Dual Liquid Biopsy Biomarkers for Immunotherapy Outcomes in Advanced Non–Small Cell Lung Cancer: A Retrospective Study

Key Points

The study aims to evaluate the relationship between dual biomarkers PD-L1 on circulating tumor cells and PD-1 on CD8+ T cells with immunotherapy outcomes in advanced non-small cell lung cancer.
Retrospective analysis of stage IIIB–IV NSCLC patients treated with anti-PD-1/PD-L1 from January 2022 to December 2023.
Included 126 patients with evaluable dual-biomarker testing and successful assessments of CTC PD-L1 and CD8+ T-cell PD-1 using flow cytometry.
Stratified patients based on CTC PD-L1 status and CD8+ PD-1 (high/low).
57 patients (45.2%) were CTC PD-L1-positive.
Median progression-free survival (PFS) was significantly longer in the PD-L1+/PD-1high group (14.2 months) than in other groups (8.5, 6.3, and 4.8 months; p<0.001).
Objective response rates (ORR) were noted as 41.9%, 30.8%, 22.9%, and 14.7% across groups (p=0.021).
Dual-biomarker status was independently associated with PFS (HR=0.48) and overall survival (OS) (HR=0.53) after adjusting for covariates.

Abstract

Background: Circulating tumor cells (CTCs) and peripheral T-cell immune checkpoints offer minimally invasive biomarkers for immune checkpoint inhibitor (ICI) therapy. We assessed whether a dual biomarker combining PD-L1 on CTCs and PD-1 on circulating CD8 + T cells is associated with outcomes in advanced non–small cell lung cancer (NSCLC). Methods: We retrospectively enrolled stage IIIB–IV NSCLC patients treated with anti-PD-1/PD-L1 agents (any line) from January 2022 to December 2023. Eligibility required pretreatment blood and evaluable dual-biomarker testing; all 126 included patients had successful CTC assessment and flow-cytometric CD8 + T-cell PD-1 measurement. Patients were classified as CTC PD-L1–positive if ≥ 1 CTC showed membranous and/or cytoplasmic PD-L1 staining. CD8 + PD-1high was defined by the cohort median PD-1+ fraction (35.6%). Patients were stratified by CTC PD-L1 status and CD8 + PD-1 (high/low). The primary endpoint was progression-free survival (PFS); overall survival (OS) and objective response rate (ORR) were secondary endpoints. Results: Fifty-seven patients (45.2%) were CTC PD-L1–positive. Median PFS was longest in the PD-L1 + /PD-1high group (14.2 months) versus the other three groups (8.5, 6.3, and 4.8 months; p< 0.001). ORR followed a similar gradient (41.9%, 30.8%, 22.9%, and 14.7%; p=0.021). After adjustment for baseline covariates, dual-biomarker status remained independently associated with PFS (HR=0.48, 95% CI 0.32– 0.72; p< 0.001) and OS (HR=0.53, 95% CI 0.35– 0.80; p=0.002). Conclusion: This dual liquid-biopsy approach was associated with response and survival in this retrospective advanced NSCLC cohort receiving ICIs, supporting its potential for prognostic stratification; prospective validation is needed. Keywords: circulating tumor cells, non-small cell lung cancer, CD8 + T cells, PD-L1, PD-1, immunotherapy, liquid biopsy, predictive biomarkers

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