Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion
T cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response....
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MDPI AG
2025-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/14/12/901 |
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| author | Dennis Christoph Harrer Tim Schlierkamp-Voosen Markus Barden Hong Pan Maria Xydia Wolfgang Herr Jan Dörrie Niels Schaft Hinrich Abken |
| author_facet | Dennis Christoph Harrer Tim Schlierkamp-Voosen Markus Barden Hong Pan Maria Xydia Wolfgang Herr Jan Dörrie Niels Schaft Hinrich Abken |
| author_sort | Dennis Christoph Harrer |
| collection | DOAJ |
| description | T cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response. To extend T cell cytotoxic capacities, we engineered CAR T cells to constitutively release an immunostimulatory variant of soluble SLAMF6. While wild-type SLAMF6 induces T cell exhaustion, CAR T cells with the soluble Δ17-65 SLAMF6 variant exhibited refined, CAR redirected functionality compared to canonical CAR T cells. CD28-ζ CAR T cells releasing soluble SLAMF6 increased IFN-γ secretion and augmented CD25 upregulation on CD4<sup>+</sup> CAR T cells upon CAR engagement by pancreatic carcinoma and melanoma cells. Moreover, under conditions of repetitive antigen encounter, SLAMF6-secreting CAR T cells evinced superior cytotoxic capacity in the long term. Mechanistically, SLAMF6-secreting CAR T cells showed predominantly a central memory phenotype, a PD-1<sup>-</sup> TIGIT<sup>-</sup> double negative profile, and reduced expression of exhaustion-related transcription factors IRF-4 and TOX with augmented amplification and persistence capacities. Overall, CAR T cells engineered with the release isoform 2 SLAMF6 establish an auto-stimulatory loop with the potential to boost the cytolytic attack against solid tumors. |
| format | Article |
| id | doaj-art-5b57524fa5d54d5fb65b232d350f50cf |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-5b57524fa5d54d5fb65b232d350f50cf2025-08-20T03:27:00ZengMDPI AGCells2073-44092025-06-01141290110.3390/cells14120901Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory FashionDennis Christoph Harrer0Tim Schlierkamp-Voosen1Markus Barden2Hong Pan3Maria Xydia4Wolfgang Herr5Jan Dörrie6Niels Schaft7Hinrich Abken8Department of Internal Medicine III—Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, GermanyLeibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, GermanyLeibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, GermanyLeibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, GermanyLeibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, GermanyDepartment of Internal Medicine III—Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, GermanyBavarian Cancer Research Center (BZKF), 91054 Erlangen, GermanyBavarian Cancer Research Center (BZKF), 91054 Erlangen, GermanyLeibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, GermanyT cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response. To extend T cell cytotoxic capacities, we engineered CAR T cells to constitutively release an immunostimulatory variant of soluble SLAMF6. While wild-type SLAMF6 induces T cell exhaustion, CAR T cells with the soluble Δ17-65 SLAMF6 variant exhibited refined, CAR redirected functionality compared to canonical CAR T cells. CD28-ζ CAR T cells releasing soluble SLAMF6 increased IFN-γ secretion and augmented CD25 upregulation on CD4<sup>+</sup> CAR T cells upon CAR engagement by pancreatic carcinoma and melanoma cells. Moreover, under conditions of repetitive antigen encounter, SLAMF6-secreting CAR T cells evinced superior cytotoxic capacity in the long term. Mechanistically, SLAMF6-secreting CAR T cells showed predominantly a central memory phenotype, a PD-1<sup>-</sup> TIGIT<sup>-</sup> double negative profile, and reduced expression of exhaustion-related transcription factors IRF-4 and TOX with augmented amplification and persistence capacities. Overall, CAR T cells engineered with the release isoform 2 SLAMF6 establish an auto-stimulatory loop with the potential to boost the cytolytic attack against solid tumors.https://www.mdpi.com/2073-4409/14/12/901CAR T celladoptive T cell therapycheckpointstimulationexhaustion |
| spellingShingle | Dennis Christoph Harrer Tim Schlierkamp-Voosen Markus Barden Hong Pan Maria Xydia Wolfgang Herr Jan Dörrie Niels Schaft Hinrich Abken Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion Cells CAR T cell adoptive T cell therapy checkpoint stimulation exhaustion |
| title | Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion |
| title_full | Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion |
| title_fullStr | Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion |
| title_full_unstemmed | Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion |
| title_short | Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion |
| title_sort | chimeric antigen receptor car t cells releasing soluble slamf6 isoform 2 gain superior anti cancer cell functionality in an auto stimulatory fashion |
| topic | CAR T cell adoptive T cell therapy checkpoint stimulation exhaustion |
| url | https://www.mdpi.com/2073-4409/14/12/901 |
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