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<p>Peripheral blood (PB) is a source of tumor-infiltrating tumor-reactive T cells (TR-T). Circulating TR-Ts (cTR-T) in PB are expected to contribute to the efficacy of immune checkpoint inhibitors (ICIs), but their phenotype remains poorly understood. Here we analyse paired tumor-infiltrating and peripheral CD8<sup>+</sup> T cells from patients with non-small cell lung carcinoma (NSCLC), using single-cell RNA and T cell receptor (TCR) sequencing. Tumor-infiltrating TR-Ts are defined based on the reported TR-T-associated gene signatures. Using their TCR sequence as a barcode, we identify cTR-Ts and their specific surface markers, including CD49a, CD49b, and HLA-DR. Trajectory analysis assigns a progenitor-like phenotype to cTR-Ts, suggesting a potential developmental relationship with tumor-infiltrating TR-Ts. By single-cell transcriptomic and flow cytometric analysis on an ICI-treated cohort we show that pre-treatment cTR-Ts in responders are characterized by a relatively low expression of exhaustion-related CD38. Following the first dose, cTR-Ts of responders transit towards a <i>TCF7</i><sup>+</sup> stem-like phenotype. Additionally, we validate cTR-T’s phenotypic changes following PD-1 blockade therapy in mouse tumor models with artificial antigen. These findings suggest that the phenotypic state and transition of cTR-Ts may reflect their functional potential after tumor infiltration and are associated with therapeutic outcomes of ICIs.</p>

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Phenotype of circulating tumor-reactive T cells predicts immune checkpoint inhibitor response in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Katsuhiro Ito,
  • Kei Iida,
  • Tomoko Hirano,
  • Merrin Man Long Leong,
  • Kenji Morii,
  • Toshi Menju,
  • Hiroshi Date,
  • Hiroaki Ozasa,
  • Hironori Yoshida,
  • Toyohiro Hirai,
  • Shusuke Kawashima,
  • Kazuhiro Aoyama,
  • Yuka Saeki,
  • Takashi Inozume,
  • Takashi Kobayashi,
  • Kenji Chamoto,
  • Tomonori Yaguchi

摘要

Peripheral blood (PB) is a source of tumor-infiltrating tumor-reactive T cells (TR-T). Circulating TR-Ts (cTR-T) in PB are expected to contribute to the efficacy of immune checkpoint inhibitors (ICIs), but their phenotype remains poorly understood. Here we analyse paired tumor-infiltrating and peripheral CD8+ T cells from patients with non-small cell lung carcinoma (NSCLC), using single-cell RNA and T cell receptor (TCR) sequencing. Tumor-infiltrating TR-Ts are defined based on the reported TR-T-associated gene signatures. Using their TCR sequence as a barcode, we identify cTR-Ts and their specific surface markers, including CD49a, CD49b, and HLA-DR. Trajectory analysis assigns a progenitor-like phenotype to cTR-Ts, suggesting a potential developmental relationship with tumor-infiltrating TR-Ts. By single-cell transcriptomic and flow cytometric analysis on an ICI-treated cohort we show that pre-treatment cTR-Ts in responders are characterized by a relatively low expression of exhaustion-related CD38. Following the first dose, cTR-Ts of responders transit towards a TCF7+ stem-like phenotype. Additionally, we validate cTR-T’s phenotypic changes following PD-1 blockade therapy in mouse tumor models with artificial antigen. These findings suggest that the phenotypic state and transition of cTR-Ts may reflect their functional potential after tumor infiltration and are associated with therapeutic outcomes of ICIs.