Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion
Abstract Multiple myeloma (MM) is a plasma cell‐derived malignancy. While immune checkpoint blockade immunotherapy has advanced myeloma treatment, chemotherapy remains the primary therapy. How chemotherapy interacts with immune checkpoint expression and impacts immunotherapy efficacy remains unclear...
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411082 |
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| author | Rui Chen Zongwei Li Zhihong Fang Zou Li Daoyan Yang Yuan Li Shurong Liu Zhiqiang Liu Rui Liu Huan Liu |
| author_facet | Rui Chen Zongwei Li Zhihong Fang Zou Li Daoyan Yang Yuan Li Shurong Liu Zhiqiang Liu Rui Liu Huan Liu |
| author_sort | Rui Chen |
| collection | DOAJ |
| description | Abstract Multiple myeloma (MM) is a plasma cell‐derived malignancy. While immune checkpoint blockade immunotherapy has advanced myeloma treatment, chemotherapy remains the primary therapy. How chemotherapy interacts with immune checkpoint expression and impacts immunotherapy efficacy remains unclear. Here it is discovered that chemotherapeutic drugs induce DNA damage and activate the cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. This activation promotes phosphorylation of the interferon regulatory factor 7 (IRF7), which binds to the promoter region of SERTA‐containing domain 1 (SERTAD1, also called SEI1) gene to enhance its transcription. The SEI1 directly interacts with the enhancer factors CREB‐binding protein (CBP)/p300 and RNA polymerase II (pol II)‐associated factor 1 (PAF1) complex, promoting transcriptional activity and leading to upregulation of programmed death ligand‐1 (PD‐L1) and immune escape in myeloma. Both in vitro and in vivo experiments demonstrate that treating myeloma cells with PD‐L1 antibodies post‐chemotherapy significantly enhances the killing efficiency of activated T cells, compared to sequential treatment with chemotherapy and PD‐L1 antibodies. This research not only uncovers a pivotal regulatory mechanism of PD‐L1 upregulation but also provides a compelling rationale for the integration of chemotherapy and immunotherapy in myeloma treatment. |
| format | Article |
| id | doaj-art-be97c48cffbc4e78a9b675d829f6aca0 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-be97c48cffbc4e78a9b675d829f6aca02025-08-20T02:26:18ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202411082Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune EvasionRui Chen0Zongwei Li1Zhihong Fang2Zou Li3Daoyan Yang4Yuan Li5Shurong Liu6Zhiqiang Liu7Rui Liu8Huan Liu9Cancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaSchool of Life Sciences Anhui Medical University Hefei Anhui 230032 ChinaDepartment of Hematology The First Affiliated Hospital of Xiamen University and Institute of Hematology School of Medicine Xiamen University Xiamen 361102 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaShandong Provincial Key Laboratory of Radiation Oncology Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan 250117 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaCancer Research Center School of Medicine Xiamen University Xiamen 361102 ChinaAbstract Multiple myeloma (MM) is a plasma cell‐derived malignancy. While immune checkpoint blockade immunotherapy has advanced myeloma treatment, chemotherapy remains the primary therapy. How chemotherapy interacts with immune checkpoint expression and impacts immunotherapy efficacy remains unclear. Here it is discovered that chemotherapeutic drugs induce DNA damage and activate the cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. This activation promotes phosphorylation of the interferon regulatory factor 7 (IRF7), which binds to the promoter region of SERTA‐containing domain 1 (SERTAD1, also called SEI1) gene to enhance its transcription. The SEI1 directly interacts with the enhancer factors CREB‐binding protein (CBP)/p300 and RNA polymerase II (pol II)‐associated factor 1 (PAF1) complex, promoting transcriptional activity and leading to upregulation of programmed death ligand‐1 (PD‐L1) and immune escape in myeloma. Both in vitro and in vivo experiments demonstrate that treating myeloma cells with PD‐L1 antibodies post‐chemotherapy significantly enhances the killing efficiency of activated T cells, compared to sequential treatment with chemotherapy and PD‐L1 antibodies. This research not only uncovers a pivotal regulatory mechanism of PD‐L1 upregulation but also provides a compelling rationale for the integration of chemotherapy and immunotherapy in myeloma treatment.https://doi.org/10.1002/advs.202411082chemotherapyimmune evasionmultiple myelomaPD‐L1SEI1 |
| spellingShingle | Rui Chen Zongwei Li Zhihong Fang Zou Li Daoyan Yang Yuan Li Shurong Liu Zhiqiang Liu Rui Liu Huan Liu Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion Advanced Science chemotherapy immune evasion multiple myeloma PD‐L1 SEI1 |
| title | Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion |
| title_full | Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion |
| title_fullStr | Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion |
| title_full_unstemmed | Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion |
| title_short | Chemotherapy‐Mediated Induction of PD‐L1 via SEI1 Facilitates Myeloma Immune Evasion |
| title_sort | chemotherapy mediated induction of pd l1 via sei1 facilitates myeloma immune evasion |
| topic | chemotherapy immune evasion multiple myeloma PD‐L1 SEI1 |
| url | https://doi.org/10.1002/advs.202411082 |
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