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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

Year: 2025

Type: article

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)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.132