Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma
Abstract The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-deriv...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39683-z |
| _version_ | 1797774125969702912 |
|---|---|
| author | Shiqun Wang Wei Yan Lingkai Kong Shuguang Zuo Jingyi Wu Chunxiao Zhu Huaping Huang Bohao He Jie Dong Jiwu Wei |
| author_facet | Shiqun Wang Wei Yan Lingkai Kong Shuguang Zuo Jingyi Wu Chunxiao Zhu Huaping Huang Bohao He Jie Dong Jiwu Wei |
| author_sort | Shiqun Wang |
| collection | DOAJ |
| description | Abstract The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM. |
| first_indexed | 2024-03-12T22:15:29Z |
| format | Article |
| id | doaj.art-fcb79dc350dd4119b18f767f89cfcceb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T22:15:29Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fcb79dc350dd4119b18f767f89cfcceb2023-07-23T11:20:11ZengNature PortfolioNature Communications2041-17232023-07-0114112110.1038/s41467-023-39683-zOncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastomaShiqun Wang0Wei Yan1Lingkai Kong2Shuguang Zuo3Jingyi Wu4Chunxiao Zhu5Huaping Huang6Bohao He7Jie Dong8Jiwu Wei9State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityDepartment of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hang ZhouState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityLiuzhou Key Laboratory of Molecular Diagnosis, Guangxi Key Laboratory of Molecular Diagnosis and Application, Affiliated Liutie Central Hospital of Guangxi Medical UniversityState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesDepartment of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hang ZhouState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing UniversityAbstract The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.https://doi.org/10.1038/s41467-023-39683-z |
| spellingShingle | Shiqun Wang Wei Yan Lingkai Kong Shuguang Zuo Jingyi Wu Chunxiao Zhu Huaping Huang Bohao He Jie Dong Jiwu Wei Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma Nature Communications |
| title | Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma |
| title_full | Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma |
| title_fullStr | Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma |
| title_full_unstemmed | Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma |
| title_short | Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma |
| title_sort | oncolytic viruses engineered to enforce cholesterol efflux restore tumor associated macrophage phagocytosis and anti tumor immunity in glioblastoma |
| url | https://doi.org/10.1038/s41467-023-39683-z |
| work_keys_str_mv | AT shiqunwang oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT weiyan oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT lingkaikong oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT shuguangzuo oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT jingyiwu oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT chunxiaozhu oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT huapinghuang oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT bohaohe oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT jiedong oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma AT jiwuwei oncolyticvirusesengineeredtoenforcecholesteroleffluxrestoretumorassociatedmacrophagephagocytosisandantitumorimmunityinglioblastoma |