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 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 neuroblastoma. Bioinformatics analysis and validation of molecular biology assays were applied to uncover the underlying mechanism. Results Three subtypes were identified using nonnegative matrix factorization (NMF), we highlighted an apoptotic status of infiltrated CD8+T cells, along with the highest CD52 expression in Cluster3 (C3) subtypes, and verified high EDF1 expression in NB cells led to Lactosylceramide (LacCer) and downstream ganglioside-GD3 accumulation, which subsequently increased chemotaxis, CD52 and immune checkpoint expression, 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 prevented the methylation of targeted site after binding to the promoter of GD3 synthase ST8SIA1, resulting in elevated ST8SIA1 transcription. Conclusion These findings characterizes the content of GD3 in NB cells, which is regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+T cell dysfunction and inducing immune escape of NB cells. Inhibiting EDF1 may decreases suppressive factors and resolve apoptotic CD8+T cells. Controlling NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of response to current NB therapies.The integration of transcriptomic and lipidomic data provided a better understanding of the interaction between LacCer metabolites and the immune status in NB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285546 | GEO | 2025/02/12

REPOSITORIES: GEO