Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors
Abstract Inflammasomes are defense complexes that utilize cytokines and immunogenic cell death (ICD) to stimulate the immune system against pathogens. Inspired by their dual action, we present cytokine-armed pyroptosis as a strategy for boosting immune response against diverse types of tumors. To in...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55083-3 |
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| author | Sara Orehek Taja Železnik Ramuta Duško Lainšček Špela Malenšek Martin Šala Mojca Benčina Roman Jerala Iva Hafner-Bratkovič |
| author_facet | Sara Orehek Taja Železnik Ramuta Duško Lainšček Špela Malenšek Martin Šala Mojca Benčina Roman Jerala Iva Hafner-Bratkovič |
| author_sort | Sara Orehek |
| collection | DOAJ |
| description | Abstract Inflammasomes are defense complexes that utilize cytokines and immunogenic cell death (ICD) to stimulate the immune system against pathogens. Inspired by their dual action, we present cytokine-armed pyroptosis as a strategy for boosting immune response against diverse types of tumors. To induce pyroptosis, we utilize designed tightly regulated gasdermin D variants comprising different pore-forming capabilities and diverse modes of activation, representing a toolbox of ICD inducers. We demonstrate that the electrogenic transfer of ICD effector-encoding plasmids into mouse melanoma tumors when combined with intratumoral expression of cytokines IL-1β, IL-12, or IL-18, enhanced anti-tumor immune responses. Careful selection of immunostimulatory molecules is, however, imperative as a combination of IL-1β and IL-18 antagonized the protective effect of pyroptosis by IFNγ-mediated upregulation of several immunosuppressive pathways. Additionally, we show that the intratumoral introduction of armed pyroptosis provides protection against distant tumors and proves effective across various tumor types without inducing systemic inflammation. Deconstructed inflammasomes thus serve as a powerful, tunable, and tumor-agnostic strategy to enhance antitumor response, even against the most resilient types of tumors. |
| format | Article |
| id | doaj-art-6778664f27c7443b8c92c9f7272315ad |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6778664f27c7443b8c92c9f7272315ad2025-01-05T12:35:16ZengNature PortfolioNature Communications2041-17232024-12-0115112210.1038/s41467-024-55083-3Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumorsSara Orehek0Taja Železnik Ramuta1Duško Lainšček2Špela Malenšek3Martin Šala4Mojca Benčina5Roman Jerala6Iva Hafner-Bratkovič7Department of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Analytical Chemistry, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryAbstract Inflammasomes are defense complexes that utilize cytokines and immunogenic cell death (ICD) to stimulate the immune system against pathogens. Inspired by their dual action, we present cytokine-armed pyroptosis as a strategy for boosting immune response against diverse types of tumors. To induce pyroptosis, we utilize designed tightly regulated gasdermin D variants comprising different pore-forming capabilities and diverse modes of activation, representing a toolbox of ICD inducers. We demonstrate that the electrogenic transfer of ICD effector-encoding plasmids into mouse melanoma tumors when combined with intratumoral expression of cytokines IL-1β, IL-12, or IL-18, enhanced anti-tumor immune responses. Careful selection of immunostimulatory molecules is, however, imperative as a combination of IL-1β and IL-18 antagonized the protective effect of pyroptosis by IFNγ-mediated upregulation of several immunosuppressive pathways. Additionally, we show that the intratumoral introduction of armed pyroptosis provides protection against distant tumors and proves effective across various tumor types without inducing systemic inflammation. Deconstructed inflammasomes thus serve as a powerful, tunable, and tumor-agnostic strategy to enhance antitumor response, even against the most resilient types of tumors.https://doi.org/10.1038/s41467-024-55083-3 |
| spellingShingle | Sara Orehek Taja Železnik Ramuta Duško Lainšček Špela Malenšek Martin Šala Mojca Benčina Roman Jerala Iva Hafner-Bratkovič Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors Nature Communications |
| title | Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors |
| title_full | Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors |
| title_fullStr | Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors |
| title_full_unstemmed | Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors |
| title_short | Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors |
| title_sort | cytokine armed pyroptosis induces antitumor immunity against diverse types of tumors |
| url | https://doi.org/10.1038/s41467-024-55083-3 |
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