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Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion
Harrer, Dennis Christoph
, Schlierkamp-Voosen, Tim, Barden, Markus, Pan, Hong, Xydia, Maria, Herr, Wolfgang, Dörrie, Jan, Schaft, Niels und Abken, Hinrich
(2025)
Chimeric Antigen Receptor (CAR) T Cells Releasing Soluble SLAMF6 Isoform 2 Gain Superior Anti-Cancer Cell Functionality in an Auto-Stimulatory Fashion.
Cells 14 (12), S. 901.
Veröffentlichungsdatum dieses Volltextes: 02 Jul 2025 16:24
Artikel
DOI zum Zitieren dieses Dokuments: 10.5283/epub.77038
Zusammenfassung
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 ...
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+ 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- TIGIT- 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.
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| Dokumentenart | Artikel | ||||
| Titel eines Journals oder einer Zeitschrift | Cells | ||||
| Verlag: | MDPI | ||||
|---|---|---|---|---|---|
| Band: | 14 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 12 | ||||
| Seitenbereich: | S. 901 | ||||
| Datum | 14 Juni 2025 | ||||
| Institutionen | Medizin > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
| Projekte |
Gefördert von:
Deutsche Forschungsgemeinschaft (DFG)
(324392634)
| ||||
| Identifikationsnummer |
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| Stichwörter / Keywords | CAR T cell; adoptive T cell therapy; checkpoint; stimulation; exhaustion | ||||
| Dewey-Dezimal-Klassifikation | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status | Veröffentlicht | ||||
| Begutachtet | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden | Ja | ||||
| URN der UB Regensburg | urn:nbn:de:bvb:355-epub-770385 | ||||
| Dokumenten-ID | 77038 |
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