Circulating tumor-resident T-cell clonotypes with quasi-identical TCR nucleotide sequences exhibit distinct transcriptional states and response dynamics during immune checkpoint inhibitor therapy 2180

Abstract Description The development of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, but patient responses remain inconsistent. Evidence has shown that T-cell receptors (TCRs) recognizing the same epitopes may not always be identical clonotypes but instead exhibit subtle sequence variations. However, the genomic and transcriptomic changes in these closely related T cells during immunotherapy remain unclear. In this study, we explored the evolutionary dynamics of circulating TCR clonotypes identified in tumors (TIL-TCRs) by integrating single-cell RNA/TCR sequencing from longitudinal blood samples with TCR sequencing from tumor tissue in a patient undergoing anti-CTLA-4/PD-1 therapy. We identified circulating CD8+ TIL-TCRs with identical CDR3α amino acid sequences but nearly identical CDR3β and TCR α/β (TRA/TRB) sequences. Despite their high sequence similarity, these quasi-identical TIL-TCRs displayed differential responses to immunotherapy and distinct transcriptional profiles, particularly marked by GZMK expression. Furthermore, IFNG expression within CD8A+ T-cell subsets, including these quasi-identical TIL-TCRs, increased during the patient’s response to treatment but gradually declined as acquired resistance developed. These findings highlight the interplay between tumor-infiltrating and circulating T cells, underscoring that CD8+ T cells with highly homologous TCR sequences can exhibit diverse transcriptional behaviors and dynamics in response to immunotherapy. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)