Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1
Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule‐associated protein G3BP2 is involved in the regulation of tumor‐initiating (stem) cells. In this study, we show...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.12915 |
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| author | Yanhong Zhang Changli Yue Anna M. Krichevsky Igor Garkavtsev |
| author_facet | Yanhong Zhang Changli Yue Anna M. Krichevsky Igor Garkavtsev |
| author_sort | Yanhong Zhang |
| collection | DOAJ |
| description | Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule‐associated protein G3BP2 is involved in the regulation of tumor‐initiating (stem) cells. In this study, we show that this protein also upregulates the immune checkpoint molecule PD‐L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously unknown connection between stemness programs, stress responses, and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD‐L1 co‐expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T‐cell proliferation and infiltration. Moreover, treatment of breast tumor‐bearing mice with C108 resulted in a significant survival benefit and long‐term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD‐L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anticancer immunotherapy. |
| format | Article |
| id | doaj-art-2bffcca3c06344e7b81c46abd934eaa7 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-2bffcca3c06344e7b81c46abd934eaa72025-02-04T17:30:21ZengWileyMolecular Oncology1574-78911878-02612025-02-0119255857110.1002/1878-0261.12915Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1Yanhong Zhang0Changli Yue1Anna M. Krichevsky2Igor Garkavtsev3Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School Boston MA USADepartment of Pathology Beijing Tongren Hospital Capital Medical University Beijing ChinaDepartment of Neurology Ann Romney Center for Neurologic Diseases Initiative for RNA Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USADepartment of Radiation Oncology Massachusetts General Hospital and Harvard Medical School Boston MA USAMounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule‐associated protein G3BP2 is involved in the regulation of tumor‐initiating (stem) cells. In this study, we show that this protein also upregulates the immune checkpoint molecule PD‐L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously unknown connection between stemness programs, stress responses, and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD‐L1 co‐expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T‐cell proliferation and infiltration. Moreover, treatment of breast tumor‐bearing mice with C108 resulted in a significant survival benefit and long‐term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD‐L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anticancer immunotherapy.https://doi.org/10.1002/1878-0261.12915a small molecule C108immunosuppressionPD‐L1stress granule‐associated protein G3BP2stress granules |
| spellingShingle | Yanhong Zhang Changli Yue Anna M. Krichevsky Igor Garkavtsev Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 Molecular Oncology a small molecule C108 immunosuppression PD‐L1 stress granule‐associated protein G3BP2 stress granules |
| title | Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 |
| title_full | Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 |
| title_fullStr | Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 |
| title_full_unstemmed | Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 |
| title_short | Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD‐L1 |
| title_sort | repression of the stress granule protein g3bp2 inhibits immune checkpoint molecule pd l1 |
| topic | a small molecule C108 immunosuppression PD‐L1 stress granule‐associated protein G3BP2 stress granules |
| url | https://doi.org/10.1002/1878-0261.12915 |
| work_keys_str_mv | AT yanhongzhang repressionofthestressgranuleproteing3bp2inhibitsimmunecheckpointmoleculepdl1 AT changliyue repressionofthestressgranuleproteing3bp2inhibitsimmunecheckpointmoleculepdl1 AT annamkrichevsky repressionofthestressgranuleproteing3bp2inhibitsimmunecheckpointmoleculepdl1 AT igorgarkavtsev repressionofthestressgranuleproteing3bp2inhibitsimmunecheckpointmoleculepdl1 |