Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma
Abstract The immunosuppressive tumor microenvironment of glioblastoma limits the effectiveness of most immunotherapies. Transforming growth factor (TGF)-β signaling drives tumor progression and prevents effective T cell activity. Notably, both regulatory T cells (Tregs) and effector T cells within g...
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| Format: | Article |
| Language: | English |
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Springer
2025-06-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04098-w |
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| author | Daniela Lorizio Manuela Silginer Julia Friesen Alan L. Epstein Michael Weller Patrick Roth |
| author_facet | Daniela Lorizio Manuela Silginer Julia Friesen Alan L. Epstein Michael Weller Patrick Roth |
| author_sort | Daniela Lorizio |
| collection | DOAJ |
| description | Abstract The immunosuppressive tumor microenvironment of glioblastoma limits the effectiveness of most immunotherapies. Transforming growth factor (TGF)-β signaling drives tumor progression and prevents effective T cell activity. Notably, both regulatory T cells (Tregs) and effector T cells within glioblastoma and other tumors express high levels of the immune checkpoint receptor, glucocorticoid-induced tumor necrosis factor receptor (GITR), which modulates T cell activation and function. Combining GITR agonism with TGF-β inhibition may therefore offer a compelling approach to restore anti-tumor immunity. We evaluated the combined effects of TGF-β inhibition and GITR modulation using two different GITR agonists in syngeneic mouse glioma models. GITR modulation enhanced T cell activation, as shown by increased cytokine secretion and effector T cell proliferation in vitro. Combining GITR modulation with TGF-β inhibition amplified these effects, resulting in significantly stronger immune cell-mediated tumor cell killing compared to single-agent treatments. Combination therapy improved survival of glioma-bearing mice, with a higher fraction of long-term survivors compared to monotherapy. Surviving mice resisted tumor re-challenge, indicating durable adaptive immunity. In summary, dual targeting of TGF-β and GITR pathways synergistically enhances anti-tumor immunity in glioblastoma. This novel combination strategy demonstrates clinical potential by addressing the limitations of existing immunotherapies and offering a promising approach for durable and effective glioblastoma treatment. |
| format | Article |
| id | doaj-art-569baef96f114ad6b4db24dbf29f664f |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-569baef96f114ad6b4db24dbf29f664f2025-08-20T03:42:53ZengSpringerCancer Immunology, Immunotherapy1432-08512025-06-0174811410.1007/s00262-025-04098-wSimultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in gliomaDaniela Lorizio0Manuela Silginer1Julia Friesen2Alan L. Epstein3Michael Weller4Patrick Roth5Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of ZurichDepartment of Neurology and Brain Tumor Center, University Hospital Zurich and University of ZurichDepartment of Neurology and Brain Tumor Center, University Hospital Zurich and University of ZurichDepartment of Pathology, Keck School of Medicine, University of Southern CaliforniaDepartment of Neurology and Brain Tumor Center, University Hospital Zurich and University of ZurichDepartment of Neurology and Brain Tumor Center, University Hospital Zurich and University of ZurichAbstract The immunosuppressive tumor microenvironment of glioblastoma limits the effectiveness of most immunotherapies. Transforming growth factor (TGF)-β signaling drives tumor progression and prevents effective T cell activity. Notably, both regulatory T cells (Tregs) and effector T cells within glioblastoma and other tumors express high levels of the immune checkpoint receptor, glucocorticoid-induced tumor necrosis factor receptor (GITR), which modulates T cell activation and function. Combining GITR agonism with TGF-β inhibition may therefore offer a compelling approach to restore anti-tumor immunity. We evaluated the combined effects of TGF-β inhibition and GITR modulation using two different GITR agonists in syngeneic mouse glioma models. GITR modulation enhanced T cell activation, as shown by increased cytokine secretion and effector T cell proliferation in vitro. Combining GITR modulation with TGF-β inhibition amplified these effects, resulting in significantly stronger immune cell-mediated tumor cell killing compared to single-agent treatments. Combination therapy improved survival of glioma-bearing mice, with a higher fraction of long-term survivors compared to monotherapy. Surviving mice resisted tumor re-challenge, indicating durable adaptive immunity. In summary, dual targeting of TGF-β and GITR pathways synergistically enhances anti-tumor immunity in glioblastoma. This novel combination strategy demonstrates clinical potential by addressing the limitations of existing immunotherapies and offering a promising approach for durable and effective glioblastoma treatment.https://doi.org/10.1007/s00262-025-04098-wGlioblastomaGITRLMicroenvironmentImmunotherapyImmunosuppression |
| spellingShingle | Daniela Lorizio Manuela Silginer Julia Friesen Alan L. Epstein Michael Weller Patrick Roth Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma Cancer Immunology, Immunotherapy Glioblastoma GITRL Microenvironment Immunotherapy Immunosuppression |
| title | Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma |
| title_full | Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma |
| title_fullStr | Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma |
| title_full_unstemmed | Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma |
| title_short | Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma |
| title_sort | simultaneous tgf β and gitr pathway modulation promotes anti tumor immunity in glioma |
| topic | Glioblastoma GITRL Microenvironment Immunotherapy Immunosuppression |
| url | https://doi.org/10.1007/s00262-025-04098-w |
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