FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma
Abstract Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert i...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59971-0 |
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| author | Michal Beffinger Linda Schellhammer Betül Taskoparan Sereina Deplazes Ulisse Salazar Nazanin Tatari Frauke Seehusen Leopold von Balthazar Carl Philipp Zinner Sabine Spath Tala Shekarian Marie-Françoise Ritz Marta McDaid Pascal Egloff Iwan Zimmermann Hideho Okada E. Sally Ward Jack Rohrer Markus A. Seeger Thorsten Buch Gregor Hutter Johannes vom Berg |
| author_facet | Michal Beffinger Linda Schellhammer Betül Taskoparan Sereina Deplazes Ulisse Salazar Nazanin Tatari Frauke Seehusen Leopold von Balthazar Carl Philipp Zinner Sabine Spath Tala Shekarian Marie-Françoise Ritz Marta McDaid Pascal Egloff Iwan Zimmermann Hideho Okada E. Sally Ward Jack Rohrer Markus A. Seeger Thorsten Buch Gregor Hutter Johannes vom Berg |
| author_sort | Michal Beffinger |
| collection | DOAJ |
| description | Abstract Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases. |
| format | Article |
| id | doaj-art-de6a0453d0b94caf9fb950ead1b37eb6 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-de6a0453d0b94caf9fb950ead1b37eb62025-08-20T03:08:43ZengNature PortfolioNature Communications2041-17232025-05-0116111910.1038/s41467-025-59971-0FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastomaMichal Beffinger0Linda Schellhammer1Betül Taskoparan2Sereina Deplazes3Ulisse Salazar4Nazanin Tatari5Frauke Seehusen6Leopold von Balthazar7Carl Philipp Zinner8Sabine Spath9Tala Shekarian10Marie-Françoise Ritz11Marta McDaid12Pascal Egloff13Iwan Zimmermann14Hideho Okada15E. Sally Ward16Jack Rohrer17Markus A. Seeger18Thorsten Buch19Gregor Hutter20Johannes vom Berg21Institute of Laboratory Animal Science, University of ZurichInstitute of Laboratory Animal Science, University of ZurichInstitute of Laboratory Animal Science, University of ZurichInstitute of Laboratory Animal Science, University of ZurichInstitute of Laboratory Animal Science, University of ZurichBrain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of BaselLaboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, University of ZurichInstitute of Chemistry and Biotechnology, Zurich University of Applied SciencesInstitute of Laboratory Animal Science, University of ZurichInCephalo AGBrain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of BaselBrain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of BaselBrain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of BaselInstitute of Medical Microbiology, University of ZurichInstitute of Medical Microbiology, University of ZurichDepartment of Neurological Surgery, University of CaliforniaCancer Sciences Unit, Centre for Cancer Immunology, University of SouthamptonInstitute of Chemistry and Biotechnology, Zurich University of Applied SciencesInstitute of Medical Microbiology, University of ZurichInstitute of Laboratory Animal Science, University of ZurichBrain Tumor Immunotherapy and Biology Lab, Department of Biomedicine, University Hospital and University of BaselInstitute of Laboratory Animal Science, University of ZurichAbstract Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.https://doi.org/10.1038/s41467-025-59971-0 |
| spellingShingle | Michal Beffinger Linda Schellhammer Betül Taskoparan Sereina Deplazes Ulisse Salazar Nazanin Tatari Frauke Seehusen Leopold von Balthazar Carl Philipp Zinner Sabine Spath Tala Shekarian Marie-Françoise Ritz Marta McDaid Pascal Egloff Iwan Zimmermann Hideho Okada E. Sally Ward Jack Rohrer Markus A. Seeger Thorsten Buch Gregor Hutter Johannes vom Berg FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma Nature Communications |
| title | FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma |
| title_full | FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma |
| title_fullStr | FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma |
| title_full_unstemmed | FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma |
| title_short | FcRn-silencing of IL-12Fc prevents toxicity of local IL-12 therapy and prolongs survival in experimental glioblastoma |
| title_sort | fcrn silencing of il 12fc prevents toxicity of local il 12 therapy and prolongs survival in experimental glioblastoma |
| url | https://doi.org/10.1038/s41467-025-59971-0 |
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