Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells
Abstract 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 chall...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-92209-z |
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| author | Fangxin Zhao Xuan Zhang Ying Tang Hongxin Yang Haiting Pan Beibei Li Riwen An Wu Geyemuri Chao Yang Fang Wan Jianqiang Wu |
| author_facet | Fangxin Zhao Xuan Zhang Ying Tang Hongxin Yang Haiting Pan Beibei Li Riwen An Wu Geyemuri Chao Yang Fang Wan Jianqiang Wu |
| author_sort | Fangxin Zhao |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-367f706402dc4b6882b65cc6fe1f1596 |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-367f706402dc4b6882b65cc6fe1f15962025-08-20T02:12:06ZengNature PortfolioScientific Reports2045-23222025-04-0115111510.1038/s41598-025-92209-zEngineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cellsFangxin Zhao0Xuan Zhang1Ying Tang2Hongxin Yang3Haiting Pan4Beibei Li5Riwen An6Wu Geyemuri7Chao Yang8Fang Wan9Jianqiang Wu10School of Life Sciences, Inner Mongolia UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversitySchool of Life Sciences, Inner Mongolia UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversityCollege of Basic Medicine, Inner Mongolia Medical UniversitySchool of Life Sciences, Inner Mongolia Agricultural UniversitySchool of Life Sciences, Inner Mongolia UniversityAbstract 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.https://doi.org/10.1038/s41598-025-92209-zPD-1/PD-L1TCR-TMAGE-C2CancerImmunotherapy |
| spellingShingle | Fangxin Zhao Xuan Zhang Ying Tang Hongxin Yang Haiting Pan Beibei Li Riwen An Wu Geyemuri Chao Yang Fang Wan Jianqiang Wu Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells Scientific Reports PD-1/PD-L1 TCR-T MAGE-C2 Cancer Immunotherapy |
| title | Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells |
| title_full | Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells |
| title_fullStr | Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells |
| title_full_unstemmed | Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells |
| title_short | Engineered PD-L1 co-expression in PD-1 knockout and MAGE-C2-targeting TCR-T cells augments the cytotoxic efficacy toward target cancer cells |
| title_sort | engineered pd l1 co expression in pd 1 knockout and mage c2 targeting tcr t cells augments the cytotoxic efficacy toward target cancer cells |
| topic | PD-1/PD-L1 TCR-T MAGE-C2 Cancer Immunotherapy |
| url | https://doi.org/10.1038/s41598-025-92209-z |
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