CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Abstract Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated...
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46735-5 |
| _version_ | 1797219741227548672 |
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| author | Maosheng Cheng Shuang Chen Kang Li Ganping Wang Gan Xiong Rongsong Ling Caihua Zhang Zhihui Zhang Hui Han Zhi Chen Xiaochen Wang Yu Liang Guoli Tian Ruoxing Zhou Yan Zhu Jieyi Ma Jiahong Liu Shuibin Lin Hao Xu Demeng Chen Yang Li Liang Peng |
| author_facet | Maosheng Cheng Shuang Chen Kang Li Ganping Wang Gan Xiong Rongsong Ling Caihua Zhang Zhihui Zhang Hui Han Zhi Chen Xiaochen Wang Yu Liang Guoli Tian Ruoxing Zhou Yan Zhu Jieyi Ma Jiahong Liu Shuibin Lin Hao Xu Demeng Chen Yang Li Liang Peng |
| author_sort | Maosheng Cheng |
| collection | DOAJ |
| description | Abstract Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy. |
| first_indexed | 2024-04-24T12:38:28Z |
| format | Article |
| id | doaj.art-73b9a51ecf3d46e89fc737e515933959 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:38:28Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-73b9a51ecf3d46e89fc737e5159339592024-04-07T11:23:07ZengNature PortfolioNature Communications2041-17232024-04-0115111710.1038/s41467-024-46735-5CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancerMaosheng Cheng0Shuang Chen1Kang Li2Ganping Wang3Gan Xiong4Rongsong Ling5Caihua Zhang6Zhihui Zhang7Hui Han8Zhi Chen9Xiaochen Wang10Yu Liang11Guoli Tian12Ruoxing Zhou13Yan Zhu14Jieyi Ma15Jiahong Liu16Shuibin Lin17Hao Xu18Demeng Chen19Yang Li20Liang Peng21Department of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityInstitute for Advanced Study, Shenzhen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityHospital of Stomatology, Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversitySenior Department of Oncology, the Fifth Medical Center of PLA General HospitalDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityState Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan UniversityDepartment of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen UniversityDepartment of Genetics, School of Life Sciences, Anhui Medical UniversitySenior Department of Oncology, the Fifth Medical Center of PLA General HospitalAbstract Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.https://doi.org/10.1038/s41467-024-46735-5 |
| spellingShingle | Maosheng Cheng Shuang Chen Kang Li Ganping Wang Gan Xiong Rongsong Ling Caihua Zhang Zhihui Zhang Hui Han Zhi Chen Xiaochen Wang Yu Liang Guoli Tian Ruoxing Zhou Yan Zhu Jieyi Ma Jiahong Liu Shuibin Lin Hao Xu Demeng Chen Yang Li Liang Peng CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer Nature Communications |
| title | CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer |
| title_full | CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer |
| title_fullStr | CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer |
| title_full_unstemmed | CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer |
| title_short | CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer |
| title_sort | cd276 dependent efferocytosis by tumor associated macrophages promotes immune evasion in bladder cancer |
| url | https://doi.org/10.1038/s41467-024-46735-5 |
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