Pre-treatment peripheral blood TCR repertoire as a predictor of response in patients with NSCLC treated with immunochemotherapy.

Background: Although there has been progress in developing T-cell receptor (TCR)-based biomarkers to predict clinical benefit (CB) in patients treated with immune checkpoint blockade (ICB) therapy, studies on the circulating TCR repertoire in non-small cell lung cancer (NSCLC) remain limited. Therefore, further investigation and validation of the TCR repertoire as a potential biomarker for predicting the benefit of immune checkpoint inhibitor therapy are needed.

Methods: Blood samples were collected from patients with advanced NSCLC before initiating anti-programmed cell death 1 (anti-PD-1) antibody treatment in combination with chemotherapy. Next-generation sequencing was used to analyze the complementarity-determining region 3 (CDR3) of the T cell receptor beta (TRB)gene. Richness, Shannon diversity indices, and the usage of variable and joining genes were studied. TCR repertoire metrics were then correlated with CB, progression-free survival (PFS), and overall survival (OS).

Results: We found that the number of unique clones and richness index were comparable between the clinical benefit (CB) and no-clinical benefit (non-CB) groups. A high number of unique clones and a higher richness index were correlated with clinical benefit among patients treated with chemoimmunotherapy (ChIO) therapy. However, despite this association, a statistically non-significant correlation was observed between any of the TCR repertoire metrics and PFS or OS in patients treated with ChIO. Higher TRBJ2-1 frequencies were associated with clinical benefit. Most clonotypes contained CDR3 fragments ranging from 12 to 16 amino acids in length. However, visualization of the relative similarity of TCR repertoires using multidimensional scaling analysis revealed that TCR repertoires of the benefit group could not be separated from those of the benefit group.

Conclusion: The circulating TCR repertoire may serve as a potential tool for predicting clinical outcomes of anti-PD-1 plus chemotherapy, aiding the selection of patients likely to experience clinical benefit. Further large-scale prospective studies are required to validate these findings.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12885-025-14523-z.