EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma
Abstract Background Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key fact...
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BMC
2025-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03307-9 |
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| author | Di Li Meng Li Zhenjian Zhuo Huiqin Guo Weixin Zhang Yile Xu Hai-Yun Wang Jiabin Liu Huimin Xia Huiran Lin Jue Tang Jing He Lei Miao |
| author_facet | Di Li Meng Li Zhenjian Zhuo Huiqin Guo Weixin Zhang Yile Xu Hai-Yun Wang Jiabin Liu Huimin Xia Huiran Lin Jue Tang Jing He Lei Miao |
| author_sort | Di Li |
| collection | DOAJ |
| description | Abstract Background Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8+ T cells remain elusive. Methods We performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal NB. Bioinformatics analysis and biological validation were applied to uncover the underlying mechanism. Results Three subtypes were identified using nonnegative matrix factorization (NMF), among which we highlighted an apoptotic status of infiltrated CD8+ T cells, along with the highest CD52 and EDF1 expression in Cluster3 (C3) subtypes. It was verified that high EDF1 expression in NB cells led to Lactosylceramide (LacCer) accumulation, as well as downstream ganglioside-GD3, which subsequently increased the expression of CD52 and immune checkpoint genes, chemotaxis, and apoptosis-related events in activated CD8+T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which further prevented the promoter region methylation of ST8SIA1, to elevate its transcription. Conclusion These findings characterize abundant GD3 in NB cells, which regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+ T cell dysfunction. Inhibition of EDF1 may reduce suppressive factors and prevent immune escape of NB cells. Modulating NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of responses to current NB therapies. The integration of transcriptomic and lipidomic data offers a more comprehensive understanding of the interaction between LacCer metabolites and the immune status in NB. Graphical Abstract |
| format | Article |
| id | doaj-art-4067a68a3bf34411944d3727b0d7c5c9 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-4067a68a3bf34411944d3727b0d7c5c92025-02-09T12:59:48ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-02-0144112010.1186/s13046-025-03307-9EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastomaDi Li0Meng Li1Zhenjian Zhuo2Huiqin Guo3Weixin Zhang4Yile Xu5Hai-Yun Wang6Jiabin Liu7Huimin Xia8Huiran Lin9Jue Tang10Jing He11Lei Miao12Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pathology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central RegionDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityLaboratory Animal Management Office, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityDepartment of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical UniversityAbstract Background Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8+ T cells remain elusive. Methods We performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal NB. Bioinformatics analysis and biological validation were applied to uncover the underlying mechanism. Results Three subtypes were identified using nonnegative matrix factorization (NMF), among which we highlighted an apoptotic status of infiltrated CD8+ T cells, along with the highest CD52 and EDF1 expression in Cluster3 (C3) subtypes. It was verified that high EDF1 expression in NB cells led to Lactosylceramide (LacCer) accumulation, as well as downstream ganglioside-GD3, which subsequently increased the expression of CD52 and immune checkpoint genes, chemotaxis, and apoptosis-related events in activated CD8+T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which further prevented the promoter region methylation of ST8SIA1, to elevate its transcription. Conclusion These findings characterize abundant GD3 in NB cells, which regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+ T cell dysfunction. Inhibition of EDF1 may reduce suppressive factors and prevent immune escape of NB cells. Modulating NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of responses to current NB therapies. The integration of transcriptomic and lipidomic data offers a more comprehensive understanding of the interaction between LacCer metabolites and the immune status in NB. Graphical Abstracthttps://doi.org/10.1186/s13046-025-03307-9EDF1NeuroblastomaCD8+ T cell dysfunctionLacCer metabolismGD3 |
| spellingShingle | Di Li Meng Li Zhenjian Zhuo Huiqin Guo Weixin Zhang Yile Xu Hai-Yun Wang Jiabin Liu Huimin Xia Huiran Lin Jue Tang Jing He Lei Miao EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma Journal of Experimental & Clinical Cancer Research EDF1 Neuroblastoma CD8+ T cell dysfunction LacCer metabolism GD3 |
| title | EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma |
| title_full | EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma |
| title_fullStr | EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma |
| title_full_unstemmed | EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma |
| title_short | EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma |
| title_sort | edf1 accelerates ganglioside gd3 accumulation to boost cd52 mediated cd8 t cell dysfunction in neuroblastoma |
| topic | EDF1 Neuroblastoma CD8+ T cell dysfunction LacCer metabolism GD3 |
| url | https://doi.org/10.1186/s13046-025-03307-9 |
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