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<p>To elucidate the immunological mechanisms underlying T cell exhaustion in papillary thyroid carcinoma (PTC) by integrating bulk and single-cell transcriptomic data, with a particular focus on the NECTIN–TIGIT interaction as a potential driver of immune evasion. Papillary thyroid carcinoma, while often indolent, can recur or progress in certain patients. Increasing evidence suggests that immune evasion within the tumor microenvironment (TME) plays a central role in PTC pathogenesis. Among the various immune checkpoint pathways, the NECTIN–TIGIT axis has emerged in other cancers as a key mediator of T cell dysfunction; yet, its role in PTC remains poorly characterized. We conducted an integrated analysis of publicly available bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) datasets from the gene expression omnibus (GEO). Differential gene expression, cell-type annotation, exhaustion marker profiling, and ligand–receptor interaction analyses were employed to investigate immune cell states and intercellular signaling. Drug sensitivity data from multiple pharmacogenomic databases were used to assess therapeutic implications. Our analysis revealed a high expression of TIGIT and associated exhaustion markers (PDCD1, CTLA4, and TOX) in PTC-infiltrating T cells, alongside a dominant presence of NECTIN2/3 in epithelial and endothelial compartments. The NECTIN–TIGIT interaction was found to suppress CD226 co-stimulatory signaling, promoting T cell exhaustion. Endothelial cells were identified as key ligands senders, creating an immunosuppressive microenvironment. Drug sensitivity correlations further suggested that TIGIT-mediated exhaustion may influence therapeutic responsiveness. This study identifies the NECTIN–TIGIT axis as a novel immunoregulatory pathway contributing to T cell exhaustion in PTC. These findings provide mechanistic insights into immune evasion and suggest NECTIN–TIGIT signaling as a potential biomarker and therapeutic target. Future wet-laboratory validation and clinical studies are needed to confirm the translational relevance of this axis in thyroid cancer management.</p>

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Integrated bulk and single-cell transcriptomic profiling reveals NECTIN–TIGIT interaction underlies T cell exhaustion in papillary thyroid carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Ahmad Golestanifar,
  • Mohammad Reza Seyedtaghia,
  • Pegah Mousavi

摘要

To elucidate the immunological mechanisms underlying T cell exhaustion in papillary thyroid carcinoma (PTC) by integrating bulk and single-cell transcriptomic data, with a particular focus on the NECTIN–TIGIT interaction as a potential driver of immune evasion. Papillary thyroid carcinoma, while often indolent, can recur or progress in certain patients. Increasing evidence suggests that immune evasion within the tumor microenvironment (TME) plays a central role in PTC pathogenesis. Among the various immune checkpoint pathways, the NECTIN–TIGIT axis has emerged in other cancers as a key mediator of T cell dysfunction; yet, its role in PTC remains poorly characterized. We conducted an integrated analysis of publicly available bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) datasets from the gene expression omnibus (GEO). Differential gene expression, cell-type annotation, exhaustion marker profiling, and ligand–receptor interaction analyses were employed to investigate immune cell states and intercellular signaling. Drug sensitivity data from multiple pharmacogenomic databases were used to assess therapeutic implications. Our analysis revealed a high expression of TIGIT and associated exhaustion markers (PDCD1, CTLA4, and TOX) in PTC-infiltrating T cells, alongside a dominant presence of NECTIN2/3 in epithelial and endothelial compartments. The NECTIN–TIGIT interaction was found to suppress CD226 co-stimulatory signaling, promoting T cell exhaustion. Endothelial cells were identified as key ligands senders, creating an immunosuppressive microenvironment. Drug sensitivity correlations further suggested that TIGIT-mediated exhaustion may influence therapeutic responsiveness. This study identifies the NECTIN–TIGIT axis as a novel immunoregulatory pathway contributing to T cell exhaustion in PTC. These findings provide mechanistic insights into immune evasion and suggest NECTIN–TIGIT signaling as a potential biomarker and therapeutic target. Future wet-laboratory validation and clinical studies are needed to confirm the translational relevance of this axis in thyroid cancer management.