Homo sapiens Raw sequence reads. Homo sapiens

Background: Although T-cell receptor (TCR)-based biomarkers have the potential to predict the clinical benefit for patients treated with immune checkpoint blockade (ICB) therapy, the circulating TCR repertoire is valuable as a marker for patients with non-small cell lung cancer (NSCLC) who could benefit from immunochemotherapy is very limited. Therefore, cancer-specific TCR-based biomarkers for predicting the efficacy of immune checkpoint inhibitors require further investigation and validation.Methods: Thirty-two patients with advanced NSCLC received PD-1 antibody treatment in combination with chemotherapy. Blood samples were obtained before treatment initiation. When disease progression was confirmed, patients were classified into a response or progression group according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The TCR repertoire was analyzed using next-generation sequencing of the complementarity-determining region 3 (CDR3) in TRB. Richness and Shannon indices and variable (V) and joining (J) gene usage were used to measure the diversity of the TCR repertoire.Results: The clonal expansion and diversity of the CD4+ T-cell repertoire were comparable between the clinical benefit (CB) and no-clinical benefit (non-CB) groups. The proportion of expanded clones, an indicator of antigen-driven clonal expansion, was significantly higher in the CB group. Furthermore, we found a trend toward longer progression-free survival among patients with higher richness and Shannon indices at baseline. Higher TRBJ2-1 frequencies were associated with clinical benefits. The length distributions of the CDR3 amino acid sequences at positions 14, 15, and 28 significantly differed between the two groups. Visualization of the relative similarity of TCR repertoires using multidimensional scaling analysis showed that the TCR repertoires of the CB group were not significantly different from those in the non-CB group.Conclusion: Our results collectively suggest that the circulating TCR repertoire of CB patients differed from that in no-CB patients. Moreover, the circulating TCR repertoire can help predict the clinical outcomes of anti-PD-1 combination therapy, which will help select patients who are likely to have a clinical benefit. Further large-scale prospective studies are required to confirm these findings.