Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation
Abstract Conventional chemotherapy- and radiotherapy-induced cancer senescence, which is characterized by poor proliferation, drug resistance, and senescence-associated secretory phenotype, has gained attention as contributing to cancer relapse and the development of an immunosuppressive tumor micro...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54132-1 |
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| author | Hyun Jung Hwang Donghee Kang Jisoo Shin Jonghun Jung Soyeon Ko Kyung Hee Jung Soon-Sun Hong Ji Eun Park Myung Jin Oh Hyun Joo An Wen-Hao Yang Young-Gyu Ko Jong-Ho Cha Jae-Seon Lee |
| author_facet | Hyun Jung Hwang Donghee Kang Jisoo Shin Jonghun Jung Soyeon Ko Kyung Hee Jung Soon-Sun Hong Ji Eun Park Myung Jin Oh Hyun Joo An Wen-Hao Yang Young-Gyu Ko Jong-Ho Cha Jae-Seon Lee |
| author_sort | Hyun Jung Hwang |
| collection | DOAJ |
| description | Abstract Conventional chemotherapy- and radiotherapy-induced cancer senescence, which is characterized by poor proliferation, drug resistance, and senescence-associated secretory phenotype, has gained attention as contributing to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the association between cancer senescence and anti-tumor immunity is not fully understood. Here, we demonstrate that senescent cancer cells increase the level of PD-L1 by promoting its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion reduces this elevated level of PD-L1 through the ER-lysosome-associated degradation pathway, thereby increasing the susceptibility of senescent cancer cells to T-cell-mediated killing. Consistently, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and boosting cytotoxic T lymphocyte activity in male mice. Moreover, ribophorin 1-targeted or anti-PD-1 therapy reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence through the activation of cytotoxic T lymphocytes. These results provide crucial insights into how senescent cancer cells can escape T-cell immunity following cancer treatment and thereby contribute to cancer recurrence. Our findings also highlight the therapeutic promise of targeting senescent cancer cells for cancer treatment. |
| format | Article |
| id | doaj-art-0298a7e6bb74498aab5b4b315bae2aa3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0298a7e6bb74498aab5b4b315bae2aa32025-01-05T12:38:34ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-54132-1Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulationHyun Jung Hwang0Donghee Kang1Jisoo Shin2Jonghun Jung3Soyeon Ko4Kyung Hee Jung5Soon-Sun Hong6Ji Eun Park7Myung Jin Oh8Hyun Joo An9Wen-Hao Yang10Young-Gyu Ko11Jong-Ho Cha12Jae-Seon Lee13Department of Molecular Medicine, Inha UniversityDepartment of Molecular Medicine, Inha UniversityProgram in Biomedical Science and Engineering, Graduate school, Inha UniversityDepartment of Molecular Medicine, Inha UniversityResearch Center for Controlling Intercellular Communication, Inha UniversityProgram in Biomedical Science and Engineering, Graduate school, Inha UniversityResearch Center for Controlling Intercellular Communication, Inha UniversityGraduate School of Analytical Science and Technology, Chungnam National UniversityGraduate School of Analytical Science and Technology, Chungnam National UniversityGraduate School of Analytical Science and Technology, Chungnam National UniversityGraduate Institute of Biomedical Sciences, China Medical UniversityDivision of Life Sciences, Korea UniversityProgram in Biomedical Science and Engineering, Graduate school, Inha UniversityDepartment of Molecular Medicine, Inha UniversityAbstract Conventional chemotherapy- and radiotherapy-induced cancer senescence, which is characterized by poor proliferation, drug resistance, and senescence-associated secretory phenotype, has gained attention as contributing to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the association between cancer senescence and anti-tumor immunity is not fully understood. Here, we demonstrate that senescent cancer cells increase the level of PD-L1 by promoting its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion reduces this elevated level of PD-L1 through the ER-lysosome-associated degradation pathway, thereby increasing the susceptibility of senescent cancer cells to T-cell-mediated killing. Consistently, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and boosting cytotoxic T lymphocyte activity in male mice. Moreover, ribophorin 1-targeted or anti-PD-1 therapy reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence through the activation of cytotoxic T lymphocytes. These results provide crucial insights into how senescent cancer cells can escape T-cell immunity following cancer treatment and thereby contribute to cancer recurrence. Our findings also highlight the therapeutic promise of targeting senescent cancer cells for cancer treatment.https://doi.org/10.1038/s41467-024-54132-1 |
| spellingShingle | Hyun Jung Hwang Donghee Kang Jisoo Shin Jonghun Jung Soyeon Ko Kyung Hee Jung Soon-Sun Hong Ji Eun Park Myung Jin Oh Hyun Joo An Wen-Hao Yang Young-Gyu Ko Jong-Ho Cha Jae-Seon Lee Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation Nature Communications |
| title | Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation |
| title_full | Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation |
| title_fullStr | Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation |
| title_full_unstemmed | Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation |
| title_short | Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation |
| title_sort | therapy induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1 dependent pd l1 upregulation |
| url | https://doi.org/10.1038/s41467-024-54132-1 |
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