Peripheral T-Cell Receptor β Repertoire Dynamics Correlate with Response to Anti-PD-L1 Therapy in Non-Small Cell Lung
Maria Goulielmaki1, Sotirios P Fortis1, Anastasia Xagara2
1Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 11522 Athens, Greece.
Cancers
|July 28, 2026
Summary
Immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) shows promise. Analyzing T-cell receptor (TCR) repertoire changes, particularly clonotype disappearance and specific gene usage, alongside blood tumor mutational burden (bTMB), can predict patient response to anti-PD-L1 therapy.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes for non-small cell lung cancer (NSCLC).
- Reliable biomarkers for predicting treatment benefit remain limited.
- Understanding the T-cell receptor (TCR) repertoire dynamics offers potential insights into treatment response.
Purpose of the Study:
- To explore the longitudinal changes in the peripheral T-cell receptor (TCR) β repertoire in NSCLC patients treated with anti-PD-L1 immunotherapy.
- To identify TCR repertoire features associated with clinical outcomes.
- To investigate the relationship between TCR dynamics, blood tumor mutational burden (bTMB), and treatment response.
Main Methods:
- Longitudinal analysis of peripheral TCR β repertoire in 28 unresectable stage IIIb NSCLC patients receiving anti-PD-L1 immunotherapy.
- Blood samples collected at baseline and three months post-treatment.
- Analysis of TCR repertoire features (diversity, richness, clonotype composition) and TRBV gene usage, correlated with clinical outcomes and bTMB.
Main Results:
- Global TCR repertoire diversity and richness did not significantly change at the cohort level.
- Individual patient analysis revealed patterns: reduced clonotype richness correlated with lower diversity and decreased convergent TCR frequency.
- Higher TRBV20-1 and lower TRBV28 gene frequencies were associated with improved survival and delayed progression.
- Disappearance of dominant TCR clonotypes during treatment correlated with longer progression-free survival (PFS).
- Higher baseline bTMB was linked to greater clonotype richness and clonotype loss.
- A subgroup with high bTMB and clonotype disappearance showed particularly favorable outcomes.
Conclusions:
- Early response to PD-L1 blockade is better reflected in subtle TCR clonotype dynamics than global repertoire shifts.
- Specific TRBV gene frequencies and the disappearance of dominant clonotypes are associated with clinical outcomes in NSCLC.
- Integrating TCR profiling with bTMB may refine patient stratification and enhance understanding of immune responses to ICB in NSCLC.
- Further validation in larger cohorts is warranted due to the exploratory nature and small sample size.
