M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance
T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we report...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2210959 |
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| author | Naisheng Zheng Tingting Wang Qin Luo Yi Liu Junyao Yang Yunlan Zhou Guohua Xie Yanhui Ma Xiangliang Yuan Lisong Shen |
| author_facet | Naisheng Zheng Tingting Wang Qin Luo Yi Liu Junyao Yang Yunlan Zhou Guohua Xie Yanhui Ma Xiangliang Yuan Lisong Shen |
| author_sort | Naisheng Zheng |
| collection | DOAJ |
| description | T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we reported that immunosuppressive M2 macrophages render cancer cells resistant to CD8+ T-cell-dependent tumor-killing refractory ICB efficacy by secreting exosomes. Proteomics and functional studies revealed that M2 macrophage-derived exosome (M2-exo) transmitted apolipoprotein E (ApoE) to cancer cells conferring ICB resistance by downregulated MHC-I expression curbing tumor intrinsic immunogenicity. Mechanistically, M2 exosomal ApoE diminished the tumor-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumor MHC-I expression. Sensitizing ICB efficacy can be achieved by the administration of ApoE ligand, EZ-482, enhancing ATPase activity of BiP to boost tumor-intrinsic immunogenicity. Therefore, ApoE may serve as a predictor and a potential therapeutic target for ICB resistance in M2-TAMs-enriched cancer patients. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumor cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumors with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy. |
| format | Article |
| id | doaj-art-59a2faa4c9524846b16d51ea577bfc7a |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-59a2faa4c9524846b16d51ea577bfc7a2025-08-20T02:57:29ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2210959M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistanceNaisheng Zheng0Tingting Wang1Qin Luo2Yi Liu3Junyao Yang4Yunlan Zhou5Guohua Xie6Yanhui Ma7Xiangliang Yuan8Lisong Shen9Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaDepartment of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. ChinaT-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we reported that immunosuppressive M2 macrophages render cancer cells resistant to CD8+ T-cell-dependent tumor-killing refractory ICB efficacy by secreting exosomes. Proteomics and functional studies revealed that M2 macrophage-derived exosome (M2-exo) transmitted apolipoprotein E (ApoE) to cancer cells conferring ICB resistance by downregulated MHC-I expression curbing tumor intrinsic immunogenicity. Mechanistically, M2 exosomal ApoE diminished the tumor-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumor MHC-I expression. Sensitizing ICB efficacy can be achieved by the administration of ApoE ligand, EZ-482, enhancing ATPase activity of BiP to boost tumor-intrinsic immunogenicity. Therefore, ApoE may serve as a predictor and a potential therapeutic target for ICB resistance in M2-TAMs-enriched cancer patients. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumor cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumors with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2210959apolipoprotein Eexosomesimmune checkpoint blockade therapyimmunogenicitymacrophages |
| spellingShingle | Naisheng Zheng Tingting Wang Qin Luo Yi Liu Junyao Yang Yunlan Zhou Guohua Xie Yanhui Ma Xiangliang Yuan Lisong Shen M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance OncoImmunology apolipoprotein E exosomes immune checkpoint blockade therapy immunogenicity macrophages |
| title | M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| title_full | M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| title_fullStr | M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| title_full_unstemmed | M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| title_short | M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| title_sort | m2 macrophage derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance |
| topic | apolipoprotein E exosomes immune checkpoint blockade therapy immunogenicity macrophages |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2210959 |
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