Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion
Abstract Background Malignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-025-03263-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849729014636216320 |
|---|---|
| author | Qinpei Cheng Xueying Zuo Zimu Wang Wanjun Lu Yuxin Jiang Jiaxin Liu Xinying Li Qiuli Xu Suhua Zhu Xin Liu Yong Song Ping Zhan Tangfeng Lv |
| author_facet | Qinpei Cheng Xueying Zuo Zimu Wang Wanjun Lu Yuxin Jiang Jiaxin Liu Xinying Li Qiuli Xu Suhua Zhu Xin Liu Yong Song Ping Zhan Tangfeng Lv |
| author_sort | Qinpei Cheng |
| collection | DOAJ |
| description | Abstract Background Malignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 blockade. Methods IL-6 levels were measured in MPE and paired serum samples from lung cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 expression. Results IL-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 pathway. Conclusion This study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management. |
| format | Article |
| id | doaj-art-c8efd103b4ee4299a10ad8412bb1778d |
| institution | DOAJ |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-c8efd103b4ee4299a10ad8412bb1778d2025-08-20T03:09:20ZengBMCRespiratory Research1465-993X2025-05-0126112010.1186/s12931-025-03263-0Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusionQinpei Cheng0Xueying Zuo1Zimu Wang2Wanjun Lu3Yuxin Jiang4Jiaxin Liu5Xinying Li6Qiuli Xu7Suhua Zhu8Xin Liu9Yong Song10Ping Zhan11Tangfeng Lv12Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityAbstract Background Malignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 blockade. Methods IL-6 levels were measured in MPE and paired serum samples from lung cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 expression. Results IL-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 pathway. Conclusion This study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management.https://doi.org/10.1186/s12931-025-03263-0Malignant pleural effusionLung cancerIL-6PD-L1Cancer-associated fibroblastImmunotherapy |
| spellingShingle | Qinpei Cheng Xueying Zuo Zimu Wang Wanjun Lu Yuxin Jiang Jiaxin Liu Xinying Li Qiuli Xu Suhua Zhu Xin Liu Yong Song Ping Zhan Tangfeng Lv Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion Respiratory Research Malignant pleural effusion Lung cancer IL-6 PD-L1 Cancer-associated fibroblast Immunotherapy |
| title | Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion |
| title_full | Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion |
| title_fullStr | Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion |
| title_full_unstemmed | Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion |
| title_short | Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion |
| title_sort | intrapleural dual blockade of il 6 and pd l1 reprograms caf dynamics and the tumor microenvironment in lung cancer associated malignant pleural effusion |
| topic | Malignant pleural effusion Lung cancer IL-6 PD-L1 Cancer-associated fibroblast Immunotherapy |
| url | https://doi.org/10.1186/s12931-025-03263-0 |
| work_keys_str_mv | AT qinpeicheng intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT xueyingzuo intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT zimuwang intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT wanjunlu intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT yuxinjiang intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT jiaxinliu intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT xinyingli intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT qiulixu intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT suhuazhu intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT xinliu intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT yongsong intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT pingzhan intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion AT tangfenglv intrapleuraldualblockadeofil6andpdl1reprogramscafdynamicsandthetumormicroenvironmentinlungcancerassociatedmalignantpleuraleffusion |