| Autor: |
Catrin Heim, Leonie Hartig, Nadine Weinelt, Laura M. Moser, Emilia Salzmann-Manrique, Michael Merker, Winfried S. Wels, Torsten Tonn, Peter Bader, Jan-Henning Klusmann, Sjoerd J.L. van Wijk, Eva Rettinger |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Oncology, Vol 32, Iss 2, Pp 200802- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2950-3299 |
| DOI: |
10.1016/j.omton.2024.200802 |
| Popis: |
Treatment resistance and immune escape are hallmarks of metastatic rhabdomyosarcoma (RMS), underscoring the urgent medical need for therapeutic agents against this disease entity as a key challenge in pediatric oncology. Chimeric antigen receptor (CAR)-based immunotherapies, such as the ErbB2 (Her2)-CAR-engineered natural killer (NK) cell line NK-92/5.28.z, provide antitumor cytotoxicity primarily through CAR-mediated cytotoxic granule release and thereafter—even in cases with low surface antigen expression or tumor escape—by triggering intrinsic NK cell-mediated apoptosis induction via additional ligand/receptors. In this study, we showed that bortezomib increased susceptibility toward apoptosis in clinically relevant RMS cell lines RH30 and RH41, and patient-derived RMS tumor organoid RMS335, by upregulation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor DR5 in these metastatic, relapsed/refractory (r/r) RMS tumors. Subsequent administration of NK-92/5.28.z cells significantly enhanced antitumor activity in vitro. Applying recombinant TRAIL instead of NK-92/5.28.z cells confirmed that the synergistic antitumor effects of the combination treatment were mediated via TRAIL. Western blot analyses indicated that the combination treatment with bortezomib and NK-92/5.28.z cells increased apoptosis by interacting with the nuclear factor κB, JNK, and caspase pathways. Overall, bortezomib pretreatment can sensitize r/r RMS tumors to CAR- and, by upregulating DR5, TRAIL-mediated cytotoxicity of NK-92/5.28.z cells. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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