Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering.
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| Format: | Artículo científico |
| Langue: | en |
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Cell reports. Medicine
2025
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| _version_ | 1868266111374458881 |
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| author | He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan |
| author_facet | He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan |
| collection | PubMed - marine biology |
| contents | Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering. He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan Humans Genetic Engineering Neoplasms Immunotherapy Animals T-Lymphocytes CD8-Positive T-Lymphocytes Mice Receptors, Chimeric Antigen Immunotherapy, Adoptive Telomerase Cell Line, Tumor We engineer a tumor-targeted genetic plasmid vector (P) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8 T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy. |
| format | Artículo científico |
| id | pubmed_41406950 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Cell reports. Medicine |
| record_format | pubmed |
| spellingShingle | Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering. He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan Humans Genetic Engineering Neoplasms Immunotherapy Animals T-Lymphocytes CD8-Positive T-Lymphocytes Mice Receptors, Chimeric Antigen Immunotherapy, Adoptive Telomerase Cell Line, Tumor Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering. He, Jiaqi Zhang, Chunguang Liang, Chao Xue, Wenchi Li, Yongheng Dai, Lili Liu, Chunyuan Zhuang, Wan-Ru Ma, Xianbin Cheng, Ran Lei, Yao Nie, Weidong Xie, Hai-Yan Humans Genetic Engineering Neoplasms Immunotherapy Animals T-Lymphocytes CD8-Positive T-Lymphocytes Mice Receptors, Chimeric Antigen Immunotherapy, Adoptive Telomerase Cell Line, Tumor We engineer a tumor-targeted genetic plasmid vector (P) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8 T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy. |
| title | Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering. |
| topic | Humans Genetic Engineering Neoplasms Immunotherapy Animals T-Lymphocytes CD8-Positive T-Lymphocytes Mice Receptors, Chimeric Antigen Immunotherapy, Adoptive Telomerase Cell Line, Tumor |
| url | https://pubmed.ncbi.nlm.nih.gov/41406950/ |