Peripheral T-Cell Receptor β Repertoire Dynamics Correlate with Response to Anti-PD-L1 Therapy in Non-Small Cell Lung Cancer

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted.