Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity
Acute myeloid leukemia (AML) remains a devastating diagnosis in clear need of therapeutic advances. Both targeted dendritic cells (DC) and particularly leukemia-derived dendritic cells (DCleu) can exert potent anti-leukemic activity. By converting AML blasts into immune activating and leukemia-antig...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1527961/full |
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| author | Hazal Aslan Rejeski Hazal Aslan Rejeski Anne Hartz Anne Hartz Elias Rackl Elias Rackl Lin Li Lin Li Christoph Schwepcke Christoph Schwepcke Kai Rejeski Kai Rejeski Christoph Schmid Christoph Schmid Andreas Rank Andreas Rank Jörg Schmohl Doris Kraemer Peter Bojko Helga Maria Schmetzer Helga Maria Schmetzer |
| author_facet | Hazal Aslan Rejeski Hazal Aslan Rejeski Anne Hartz Anne Hartz Elias Rackl Elias Rackl Lin Li Lin Li Christoph Schwepcke Christoph Schwepcke Kai Rejeski Kai Rejeski Christoph Schmid Christoph Schmid Andreas Rank Andreas Rank Jörg Schmohl Doris Kraemer Peter Bojko Helga Maria Schmetzer Helga Maria Schmetzer |
| author_sort | Hazal Aslan Rejeski |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) remains a devastating diagnosis in clear need of therapeutic advances. Both targeted dendritic cells (DC) and particularly leukemia-derived dendritic cells (DCleu) can exert potent anti-leukemic activity. By converting AML blasts into immune activating and leukemia-antigen presenting cells, DC/DCleu-generating protocols can induce immune responses against AML blasts. Such protocols combine approved response modifiers (i.e., GM-CSF and PGE1/OK-432/PGE2) that synergistically improve the conversion of AML blasts into (mature) DC/DCleu. To guide potential clinical application of these response modifiers, we analyzed three different DC-generating protocols that combine a constant GM-CSF dose with varying concentrations of PGE1 (Kit-M), OK-432 (Kit-I), and PGE2 (Kit-K). Here, we specifically aimed to assess how different response modifier concentrations impact DC/DCleu generation, immune cell activation and leukemic blast lysis. We found that all immunomodulatory kits were effective in generating mature and leukemia-derived DCs from healthy and leukemic whole blood. For Kit-M, we noted optimal generation of DC-subsets at intermediary concentration ranges of PGE1 (0.25-4.0 µg/mL), which facilitated upregulation of activated and memory T-cells upon mixed lymphocyte culture, and efficient anti-leukemic activity in cytotoxicity assays. For Kit-I, we observed DC/DCleu generation and enhanced T- and immune cell activation across a broader range of OK-432 concentrations (5-40 µg/mL), which also facilitated improved leukemic blast killing. In conclusion, our results highlight that Kit-mediated DC/DCleu generation, immune cell activation and blast lysis are dependent on the concentration of response modifiers, which will guide future clinical development. Overall, DCleu-based immunotherapy represents a promising treatment strategy for AML patients. |
| format | Article |
| id | doaj-art-d5f52b455021452b97156d7c158a258b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-d5f52b455021452b97156d7c158a258b2025-01-30T06:23:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.15279611527961Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicityHazal Aslan Rejeski0Hazal Aslan Rejeski1Anne Hartz2Anne Hartz3Elias Rackl4Elias Rackl5Lin Li6Lin Li7Christoph Schwepcke8Christoph Schwepcke9Kai Rejeski10Kai Rejeski11Christoph Schmid12Christoph Schmid13Andreas Rank14Andreas Rank15Jörg Schmohl16Doris Kraemer17Peter Bojko18Helga Maria Schmetzer19Helga Maria Schmetzer20Department of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Hematology and Oncology, University Hospital of Augsburg, Augsburg, GermanyDepartment of Hematology and Oncology, Diakonieklinikum Stuttgart, Stuttgart, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyDepartment of Hematology and Oncology, University Hospital of Augsburg, Augsburg, GermanyDepartment of Hematology and Oncology, Diakonieklinikum Stuttgart, Stuttgart, GermanyDepartment of Hematology and Oncology, St.-Josefs-Hospital, Hagen, GermanyDepartment of Hematology and Oncology, Rotkreuzklinikum Munich, Munich, GermanyDepartment of Medicine III, LMU University Hospital, LMU Munich, Munich, GermanyBavarian Cancer Research Center (BZKF), Munich Site, Munich, GermanyAcute myeloid leukemia (AML) remains a devastating diagnosis in clear need of therapeutic advances. Both targeted dendritic cells (DC) and particularly leukemia-derived dendritic cells (DCleu) can exert potent anti-leukemic activity. By converting AML blasts into immune activating and leukemia-antigen presenting cells, DC/DCleu-generating protocols can induce immune responses against AML blasts. Such protocols combine approved response modifiers (i.e., GM-CSF and PGE1/OK-432/PGE2) that synergistically improve the conversion of AML blasts into (mature) DC/DCleu. To guide potential clinical application of these response modifiers, we analyzed three different DC-generating protocols that combine a constant GM-CSF dose with varying concentrations of PGE1 (Kit-M), OK-432 (Kit-I), and PGE2 (Kit-K). Here, we specifically aimed to assess how different response modifier concentrations impact DC/DCleu generation, immune cell activation and leukemic blast lysis. We found that all immunomodulatory kits were effective in generating mature and leukemia-derived DCs from healthy and leukemic whole blood. For Kit-M, we noted optimal generation of DC-subsets at intermediary concentration ranges of PGE1 (0.25-4.0 µg/mL), which facilitated upregulation of activated and memory T-cells upon mixed lymphocyte culture, and efficient anti-leukemic activity in cytotoxicity assays. For Kit-I, we observed DC/DCleu generation and enhanced T- and immune cell activation across a broader range of OK-432 concentrations (5-40 µg/mL), which also facilitated improved leukemic blast killing. In conclusion, our results highlight that Kit-mediated DC/DCleu generation, immune cell activation and blast lysis are dependent on the concentration of response modifiers, which will guide future clinical development. Overall, DCleu-based immunotherapy represents a promising treatment strategy for AML patients.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1527961/fullblast modulationdendritic cellsleukemia-derived dendritic cellsacute myeloid leukemiaPGE1PGE2 |
| spellingShingle | Hazal Aslan Rejeski Hazal Aslan Rejeski Anne Hartz Anne Hartz Elias Rackl Elias Rackl Lin Li Lin Li Christoph Schwepcke Christoph Schwepcke Kai Rejeski Kai Rejeski Christoph Schmid Christoph Schmid Andreas Rank Andreas Rank Jörg Schmohl Doris Kraemer Peter Bojko Helga Maria Schmetzer Helga Maria Schmetzer Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity Frontiers in Immunology blast modulation dendritic cells leukemia-derived dendritic cells acute myeloid leukemia PGE1 PGE2 |
| title | Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity |
| title_full | Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity |
| title_fullStr | Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity |
| title_full_unstemmed | Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity |
| title_short | Concentration-dependent effects of immunomodulatory cocktails on the generation of leukemia-derived dendritic cells, DCleu mediated T-cell activation and on-target/off-tumor toxicity |
| title_sort | concentration dependent effects of immunomodulatory cocktails on the generation of leukemia derived dendritic cells dcleu mediated t cell activation and on target off tumor toxicity |
| topic | blast modulation dendritic cells leukemia-derived dendritic cells acute myeloid leukemia PGE1 PGE2 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1527961/full |
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