Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen
Abstract T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblast...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56547-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571519210881024 |
|---|---|
| author | Yu-Chan Chih Amelie C. Dietsch Philipp Koopmann Xiujian Ma Dennis A. Agardy Binghao Zhao Alice De Roia Alexandros Kourtesakis Michael Kilian Christopher Krämer Abigail K. Suwala Miriam Stenzinger Halvard Boenig Agnieszka Blum Victor Murcia Pienkowski Kuralay Aman Jonas P. Becker Henrike Feldmann Theresa Bunse Richard Harbottle Angelika B. Riemer Hai-Kun Liu Nima Etminan Felix Sahm Miriam Ratliff Wolfgang Wick Michael Platten Edward W. Green Lukas Bunse |
| author_facet | Yu-Chan Chih Amelie C. Dietsch Philipp Koopmann Xiujian Ma Dennis A. Agardy Binghao Zhao Alice De Roia Alexandros Kourtesakis Michael Kilian Christopher Krämer Abigail K. Suwala Miriam Stenzinger Halvard Boenig Agnieszka Blum Victor Murcia Pienkowski Kuralay Aman Jonas P. Becker Henrike Feldmann Theresa Bunse Richard Harbottle Angelika B. Riemer Hai-Kun Liu Nima Etminan Felix Sahm Miriam Ratliff Wolfgang Wick Michael Platten Edward W. Green Lukas Bunse |
| author_sort | Yu-Chan Chih |
| collection | DOAJ |
| description | Abstract T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02+ primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma. |
| format | Article |
| id | doaj-art-682c2f89a691488ab8985bb1b427bede |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-682c2f89a691488ab8985bb1b427bede2025-02-02T12:32:21ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56547-wVaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigenYu-Chan Chih0Amelie C. Dietsch1Philipp Koopmann2Xiujian Ma3Dennis A. Agardy4Binghao Zhao5Alice De Roia6Alexandros Kourtesakis7Michael Kilian8Christopher Krämer9Abigail K. Suwala10Miriam Stenzinger11Halvard Boenig12Agnieszka Blum13Victor Murcia Pienkowski14Kuralay Aman15Jonas P. Becker16Henrike Feldmann17Theresa Bunse18Richard Harbottle19Angelika B. Riemer20Hai-Kun Liu21Nima Etminan22Felix Sahm23Miriam Ratliff24Wolfgang Wick25Michael Platten26Edward W. Green27Lukas Bunse28Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), DKFZ, core center HeidelbergClinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), DKFZ, core center HeidelbergClinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), DKFZ, core center HeidelbergInstitute for Clinical Transfusion Medicine and Cell TherapyFaculty of Medicine, Goethe University, Frankfurt a.M.Ardigen, ul. Podole 76Ardigen, ul. Podole 76Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), DKFZ, core center HeidelbergClinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), DKFZ, core center HeidelbergGerman Cancer Consortium (DKTK), DKFZ, core center HeidelbergGerman Cancer Consortium (DKTK), DKFZ, core center HeidelbergDepartment of Neurosurgery, University Hospital MannheimGerman Cancer Consortium (DKTK), DKFZ, core center HeidelbergGerman Cancer Consortium (DKTK), DKFZ, core center HeidelbergGerman Cancer Consortium (DKTK), DKFZ, core center HeidelbergClinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)Abstract T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02+ primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma.https://doi.org/10.1038/s41467-025-56547-w |
| spellingShingle | Yu-Chan Chih Amelie C. Dietsch Philipp Koopmann Xiujian Ma Dennis A. Agardy Binghao Zhao Alice De Roia Alexandros Kourtesakis Michael Kilian Christopher Krämer Abigail K. Suwala Miriam Stenzinger Halvard Boenig Agnieszka Blum Victor Murcia Pienkowski Kuralay Aman Jonas P. Becker Henrike Feldmann Theresa Bunse Richard Harbottle Angelika B. Riemer Hai-Kun Liu Nima Etminan Felix Sahm Miriam Ratliff Wolfgang Wick Michael Platten Edward W. Green Lukas Bunse Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen Nature Communications |
| title | Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen |
| title_full | Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen |
| title_fullStr | Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen |
| title_full_unstemmed | Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen |
| title_short | Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen |
| title_sort | vaccine induced t cell receptor t cell therapy targeting a glioblastoma stemness antigen |
| url | https://doi.org/10.1038/s41467-025-56547-w |
| work_keys_str_mv | AT yuchanchih vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT ameliecdietsch vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT philippkoopmann vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT xiujianma vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT dennisaagardy vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT binghaozhao vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT alicederoia vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT alexandroskourtesakis vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT michaelkilian vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT christopherkramer vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT abigailksuwala vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT miriamstenzinger vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT halvardboenig vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT agnieszkablum vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT victormurciapienkowski vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT kuralayaman vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT jonaspbecker vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT henrikefeldmann vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT theresabunse vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT richardharbottle vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT angelikabriemer vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT haikunliu vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT nimaetminan vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT felixsahm vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT miriamratliff vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT wolfgangwick vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT michaelplatten vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT edwardwgreen vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen AT lukasbunse vaccineinducedtcellreceptortcelltherapytargetingaglioblastomastemnessantigen |