Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation
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)...
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Elsevier
2024-06-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924000444 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Catrin Heim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cfcc688602004da1992f3e649b5c4ffd |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-cfcc688602004da1992f3e649b5c4ffd2025-08-20T02:32:49ZengElsevierMolecular Therapy: Oncology2950-32992024-06-0132220080210.1016/j.omton.2024.200802Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulationCatrin Heim0Leonie Hartig1Nadine Weinelt2Laura M. Moser3Emilia Salzmann-Manrique4Michael Merker5Winfried S. Wels6Torsten Tonn7Peter Bader8Jan-Henning Klusmann9Sjoerd J.L. van Wijk10Eva Rettinger11Goethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyInstitute for Experimental Paediatric Haematology and Oncology (EPOH), 60528 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt am Main, a partnership between DKFZ and University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyGerman Cancer Consortium (DKTK), partner site Frankfurt am Main, a partnership between DKFZ and University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, GermanyDRK-Blutspendedienst Baden-Württemberg/Hessen gemeinnützige GmbH, 60505 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyGerman Cancer Consortium (DKTK), partner site Frankfurt am Main, a partnership between DKFZ and University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, Germany; Goethe University Frankfurt, Department of Pediatrics, 60590 Frankfurt am Main, GermanyInstitute for Experimental Paediatric Haematology and Oncology (EPOH), 60528 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt am Main, a partnership between DKFZ and University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, GermanyGoethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation and Immunology, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt am Main, a partnership between DKFZ and University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany; Universitäres Centrum für Tumorerkrankungen (UCT) Frankfurt Marburg, 60590 Frankfurt am Main, Germany; Corresponding author: Eva Rettinger, Goethe University Frankfurt, Department of Pediatrics, Division of Stem Cell Transplantation, Immunology and Intensive Care Medicine, 60590 Frankfurt am Main, Germany.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.http://www.sciencedirect.com/science/article/pii/S2950329924000444MT: Regular Issuechimeric antigen receptorimmunotherapybortezomibTRAILrhabdomyosarcoma |
| spellingShingle | 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 Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation Molecular Therapy: Oncology MT: Regular Issue chimeric antigen receptor immunotherapy bortezomib TRAIL rhabdomyosarcoma |
| title | Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation |
| title_full | Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation |
| title_fullStr | Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation |
| title_full_unstemmed | Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation |
| title_short | Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation |
| title_sort | bortezomib promotes the trail mediated killing of resistant rhabdomyosarcoma by erbb2 her2 targeted car nk 92 cells via dr5 upregulation |
| topic | MT: Regular Issue chimeric antigen receptor immunotherapy bortezomib TRAIL rhabdomyosarcoma |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924000444 |
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