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<p>Expression of the PD-1 protein by tumor cells is relatively common and has been shown to exert proliferation-inhibitory effects across various tumor types, including T-cell malignancies, non-small cell lung cancer, and colon cancer. However, harnessing this tumor suppressor pathway is challenging because PD-1 activation by PD-L1 also suppresses normal T-cell function. We hypothesized that cancer antigen-specific TCR-T cells engineered to express PD-L1 could selectively activate the PD-1 pathway in tumor cells while simultaneously preventing self-inhibition by knocking out intrinsic PD-1 expression in TCR-T cells. To test this hypothesis, we co-expressed a MAGE-C2-specific recombinant TCR and the PD-L1-encoding CD274 gene in normal human T cells in which the PDCD1 gene was knocked out. These engineered TCR-T cells targeted MAGE-C2-expressing malignant cells, activating PD-1 signaling to suppress tumor proliferation while maintaining suppressed PD-1 signaling in the TCR-T cells themselves. To evaluate the tumor-suppressive potential of this approach, we compared the efficacy of PDL1-MC2-TCR-T<sup>PD1⁻</sup> cells against subtypes lacking PD-L1 expression, PD-1 knockout, or both. Our findings demonstrated that this TCR-T model exhibited significantly enhanced cytotoxic efficacy compared to other subtypes in vitro, ex vivo, and in vivo. These results suggest that the targeted activation of intrinsic PD-1 signaling in T-cell malignancies inhibits tumor proliferation and, when combined with PD-1 inhibition in TCR-T cells, synergistically enhances their cancer-suppressing efficacy. This study provides a foundation for novel cancer treatment strategies.</p>

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Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月7日

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  • Fangxin Zhao,
  • Xuan Zhang,
  • Ying Tang,
  • Hongxin Yang,
  • Haiting Pan,
  • Beibei Li,
  • Riwen An,
  • Wu Geyemuri,
  • Chao Yang,
  • Fang Wan,
  • Jianqiang Wu

摘要

Expression of the PD-1 protein by tumor cells is relatively common and has been shown to exert proliferation-inhibitory effects across various tumor types, including T-cell malignancies, non-small cell lung cancer, and colon cancer. However, harnessing this tumor suppressor pathway is challenging because PD-1 activation by PD-L1 also suppresses normal T-cell function. We hypothesized that cancer antigen-specific TCR-T cells engineered to express PD-L1 could selectively activate the PD-1 pathway in tumor cells while simultaneously preventing self-inhibition by knocking out intrinsic PD-1 expression in TCR-T cells. To test this hypothesis, we co-expressed a MAGE-C2-specific recombinant TCR and the PD-L1-encoding CD274 gene in normal human T cells in which the PDCD1 gene was knocked out. These engineered TCR-T cells targeted MAGE-C2-expressing malignant cells, activating PD-1 signaling to suppress tumor proliferation while maintaining suppressed PD-1 signaling in the TCR-T cells themselves. To evaluate the tumor-suppressive potential of this approach, we compared the efficacy of PDL1-MC2-TCR-TPD1⁻ cells against subtypes lacking PD-L1 expression, PD-1 knockout, or both. Our findings demonstrated that this TCR-T model exhibited significantly enhanced cytotoxic efficacy compared to other subtypes in vitro, ex vivo, and in vivo. These results suggest that the targeted activation of intrinsic PD-1 signaling in T-cell malignancies inhibits tumor proliferation and, when combined with PD-1 inhibition in TCR-T cells, synergistically enhances their cancer-suppressing efficacy. This study provides a foundation for novel cancer treatment strategies.