Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway
Abstract Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antige...
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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/s41467-024-54794-x |
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| author | Yoshitaka Adachi Seitaro Terakura Masahide Osaki Yusuke Okuno Yoshitaka Sato Ken Sagou Yuki Takeuchi Hirofumi Yokota Kanae Imai Peter Steinberger Judith Leitner Ryo Hanajiri Makoto Murata Hitoshi Kiyoi |
| author_facet | Yoshitaka Adachi Seitaro Terakura Masahide Osaki Yusuke Okuno Yoshitaka Sato Ken Sagou Yuki Takeuchi Hirofumi Yokota Kanae Imai Peter Steinberger Judith Leitner Ryo Hanajiri Makoto Murata Hitoshi Kiyoi |
| author_sort | Yoshitaka Adachi |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. In this regard, CUL5 knockout CD19 CAR T cells show sustained STAT3 and STAT5 phosphorylation, as well as delayed phosphorylation and degradation of JAK1 and JAK3. In vivo, shRNA-mediated knockdown of CUL5 enhances CD19 CAR T treatment outcomes in tumor-bearing mice. Our findings thus imply that targeting CUL5 in the ubiquitin system may enhance CAR T cell effector functions to enhance immunotherapy efficacy. |
| format | Article |
| id | doaj-art-961853647bd546d5bf84a93c6f3fc51c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-961853647bd546d5bf84a93c6f3fc51c2024-12-15T12:10:23ZengNature PortfolioNature Communications2041-17232024-12-0115111410.1038/s41467-024-54794-xCullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathwayYoshitaka Adachi0Seitaro Terakura1Masahide Osaki2Yusuke Okuno3Yoshitaka Sato4Ken Sagou5Yuki Takeuchi6Hirofumi Yokota7Kanae Imai8Peter Steinberger9Judith Leitner10Ryo Hanajiri11Makoto Murata12Hitoshi Kiyoi13Department of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Virology, Nagoya City University Graduate School of Medical SciencesDepartment of Virology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDivision for Immune Receptors and T Cell Activation, Institute of Immunology, Medical University of ViennaDivision for Immune Receptors and T Cell Activation, Institute of Immunology, Medical University of ViennaDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineDepartment of Hematology and Oncology, Nagoya University Graduate School of MedicineAbstract Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. In this regard, CUL5 knockout CD19 CAR T cells show sustained STAT3 and STAT5 phosphorylation, as well as delayed phosphorylation and degradation of JAK1 and JAK3. In vivo, shRNA-mediated knockdown of CUL5 enhances CD19 CAR T treatment outcomes in tumor-bearing mice. Our findings thus imply that targeting CUL5 in the ubiquitin system may enhance CAR T cell effector functions to enhance immunotherapy efficacy.https://doi.org/10.1038/s41467-024-54794-x |
| spellingShingle | Yoshitaka Adachi Seitaro Terakura Masahide Osaki Yusuke Okuno Yoshitaka Sato Ken Sagou Yuki Takeuchi Hirofumi Yokota Kanae Imai Peter Steinberger Judith Leitner Ryo Hanajiri Makoto Murata Hitoshi Kiyoi Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway Nature Communications |
| title | Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway |
| title_full | Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway |
| title_fullStr | Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway |
| title_full_unstemmed | Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway |
| title_short | Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway |
| title_sort | cullin 5 deficiency promotes chimeric antigen receptor t cell effector functions potentially via the modulation of jak stat signaling pathway |
| url | https://doi.org/10.1038/s41467-024-54794-x |
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