RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation
Abstract Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since P...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-00828-6 |
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| author | Eugenia Crespo Liliana R. Loureiro Antonia Stammberger Lydia Hoffmann Nicole Berndt Anja Hoffmann Claudia Dagostino Karla E. G. Soto Luise Rupp Claudia Arndt Martin Schneider Claudia R. Ball Michael Bachmann Marc Schmitz Anja Feldmann |
| author_facet | Eugenia Crespo Liliana R. Loureiro Antonia Stammberger Lydia Hoffmann Nicole Berndt Anja Hoffmann Claudia Dagostino Karla E. G. Soto Luise Rupp Claudia Arndt Martin Schneider Claudia R. Ball Michael Bachmann Marc Schmitz Anja Feldmann |
| author_sort | Eugenia Crespo |
| collection | DOAJ |
| description | Abstract Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since PD-L1 is an immune checkpoint frequently upregulated by cancer cells and their microenvironment, it is a relevant target for solid tumors. Here, we introduce a novel PD-L1 RevTM capable of redirecting RevCAR T-cells to specifically target and kill PD-L1-expressing tumor cells, becoming activated and secreting pro-inflammatory cytokines. This is shown in vitro with monolayer and 3D models, including patient-derived cultures, and in vivo. Furthermore, we demonstrate in vitro and in vivo an AND-gated targeting of cells simultaneously expressing PD-L1 and another tumor-associated antigen by the Dual RevCAR system. Our findings suggest that RevCAR-mediated targeting of PD-L1 could be a promising therapeutic approach for modulating the TME and improving solid tumor treatment. |
| format | Article |
| id | doaj-art-d3405b2d74944ed09324880ab11c4415 |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-d3405b2d74944ed09324880ab11c44152025-02-09T12:09:23ZengNature Portfolionpj Precision Oncology2397-768X2025-02-019111510.1038/s41698-025-00828-6RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activationEugenia Crespo0Liliana R. Loureiro1Antonia Stammberger2Lydia Hoffmann3Nicole Berndt4Anja Hoffmann5Claudia Dagostino6Karla E. G. Soto7Luise Rupp8Claudia Arndt9Martin Schneider10Claudia R. Ball11Michael Bachmann12Marc Schmitz13Anja Feldmann14Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of TechnologyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Department for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of TechnologyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Department of General, Visceral and Transplantation Surgery, Heidelberg University HospitalDepartment for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of TechnologyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)Abstract Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since PD-L1 is an immune checkpoint frequently upregulated by cancer cells and their microenvironment, it is a relevant target for solid tumors. Here, we introduce a novel PD-L1 RevTM capable of redirecting RevCAR T-cells to specifically target and kill PD-L1-expressing tumor cells, becoming activated and secreting pro-inflammatory cytokines. This is shown in vitro with monolayer and 3D models, including patient-derived cultures, and in vivo. Furthermore, we demonstrate in vitro and in vivo an AND-gated targeting of cells simultaneously expressing PD-L1 and another tumor-associated antigen by the Dual RevCAR system. Our findings suggest that RevCAR-mediated targeting of PD-L1 could be a promising therapeutic approach for modulating the TME and improving solid tumor treatment.https://doi.org/10.1038/s41698-025-00828-6 |
| spellingShingle | Eugenia Crespo Liliana R. Loureiro Antonia Stammberger Lydia Hoffmann Nicole Berndt Anja Hoffmann Claudia Dagostino Karla E. G. Soto Luise Rupp Claudia Arndt Martin Schneider Claudia R. Ball Michael Bachmann Marc Schmitz Anja Feldmann RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation npj Precision Oncology |
| title | RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation |
| title_full | RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation |
| title_fullStr | RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation |
| title_full_unstemmed | RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation |
| title_short | RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation |
| title_sort | revcar mediated t cell response against pd l1 expressing cells turns suppression into activation |
| url | https://doi.org/10.1038/s41698-025-00828-6 |
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