Comparative Profiling of TCR Repertoires in Extranodal NK/T-Cell Lymphoma and Healthy Individuals Highlights Unique Clonal Expansions and Potential Diagnostic Biomarkers

T-cell receptor (TCR) repertoire profiling is crucial for elucidating immune responses in Extranodal NK/T-cell lymphoma (ENKTL). In this study, TCR sequencing of paraffin-embedded samples was performed using MiXCR with stringent quality control (85–95% aligned reads, 60–80% clonotype reads, < 5% low-quality reads). ENKTL patients exhibited marked clonal expansion, with the top clone frequently exceeding 40% and reduced repertoire diversity compared with healthy controls. Log–log distribution analysis showed a faster decay of low-abundance clones in ENKTL, reflecting centralized clonal structures, whereas controls displayed greater inter-sample heterogeneity. Jaccard index analysis revealed high inter-individual variability with limited clonal overlap, suggesting potential antigen-driven selection. V/J gene usage differed significantly, with ENKTL enriched for TRBV28, TRBV6-2, and TRBJ2-7, while controls preferentially used TRBV20-1 and TRBJ1-1. CDR3 length distributions were multimodal in both groups but diverged in peak positions, indicating distinct antigen-recognition profiles. Importantly, epitope recognition analysis demonstrated weaker overall responses in ENKTL, whereas controls mounted robust recognition against predicted epitopes, particularly GLCTLVAML (> 1×10⁸ reads). Collectively, these findings highlight profound alterations in TCR repertoire diversity, clonal architecture, and antigen-specific responses in ENKTL, providing molecular insights into disease immunopathogenesis and potential diagnostic and therapeutic targets.