Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma
Abstract Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45215-0 |
| _version_ | 1797274001335123968 |
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| author | Chunxiao Liu Chenhao Zhou Weiya Xia Yifan Zhou Yufan Qiu Jialei Weng Qiang Zhou Wanyong Chen Ying-Nai Wang Heng-Huan Lee Shao-Chun Wang Ming Kuang Dihua Yu Ning Ren Mien-Chie Hung |
| author_facet | Chunxiao Liu Chenhao Zhou Weiya Xia Yifan Zhou Yufan Qiu Jialei Weng Qiang Zhou Wanyong Chen Ying-Nai Wang Heng-Huan Lee Shao-Chun Wang Ming Kuang Dihua Yu Ning Ren Mien-Chie Hung |
| author_sort | Chunxiao Liu |
| collection | DOAJ |
| description | Abstract Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC. |
| first_indexed | 2024-03-07T14:52:09Z |
| format | Article |
| id | doaj.art-fec4a1384c9b4097a6c58e39022e975c |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:09Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fec4a1384c9b4097a6c58e39022e975c2024-03-05T19:39:45ZengNature PortfolioNature Communications2041-17232024-02-0115111810.1038/s41467-024-45215-0Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinomaChunxiao Liu0Chenhao Zhou1Weiya Xia2Yifan Zhou3Yufan Qiu4Jialei Weng5Qiang Zhou6Wanyong Chen7Ying-Nai Wang8Heng-Huan Lee9Shao-Chun Wang10Ming Kuang11Dihua Yu12Ning Ren13Mien-Chie Hung14Department of Liver Surgery, Center of Hepato-Pancreato-biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterDepartment of laboratory medicine, Zhujiang Hospital of Southern Medical UniversityDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan UniversityDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan UniversityDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan UniversityDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterGraduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Research Center for Cancer Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical UniversityDepartment of Liver Surgery, Center of Hepato-Pancreato-biliary Surgery, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan UniversityDepartment of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterAbstract Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.https://doi.org/10.1038/s41467-024-45215-0 |
| spellingShingle | Chunxiao Liu Chenhao Zhou Weiya Xia Yifan Zhou Yufan Qiu Jialei Weng Qiang Zhou Wanyong Chen Ying-Nai Wang Heng-Huan Lee Shao-Chun Wang Ming Kuang Dihua Yu Ning Ren Mien-Chie Hung Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma Nature Communications |
| title | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| title_full | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| title_fullStr | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| title_full_unstemmed | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| title_short | Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| title_sort | targeting alk averts ribonuclease 1 induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41467-024-45215-0 |
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