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Mapping B cells and the immune landscape of tertiary lymphoid structures reveals their clinical impact in neuroblastoma

O. Melaiu,M. Chierici,Paula Gragera,Nicolò Lazzaro,L. L. Petrilli,J. Wienke,Francisca J. Bergsma,B. M. Verhoeven,C. De Stefanis,Valentina D’Oria,M. C. Benedetti,Giovanni Barillari,R. Alaggio,M. A. De Ioris,M. Vinci,N. Baryawno,R. Carsetti,G. Jurman,Jan J. Molenaar,Franco Locatelli,D. Fruci

Published 2025 in Journal for ImmunoTherapy of Cancer

ABSTRACT

Background Immunotherapy has transformed cancer treatment, highlighting the importance of effective antitumor immunity to fight cancer. However, its success in pediatric cancer remains limited, underscoring the urgent need to identify new immunotherapeutic targets. In this study, we explored the clinical relevance of B cells and tertiary lymphoid structures (TLS) in neuroblastoma (NB), a pediatric tumor with a heterogeneous immune landscape. Methods We analyzed 87 treatment-naïve NB specimens, spanning both localized and metastatic disease previously characterized for T-cell and dendritic cell (DC) infiltration. B cells were detected by immunohistochemistry, and plasma cells were quantified using multiple immunofluorescence. Spatial organization and functional status of immune cells within TLSs were assessed by imaging mass cytometry using a 29-antibody panel. In parallel, gene expression profiles were obtained through NanoString PanCancer Immune Profiling and further validated using publicly available bulk and single-cell RNA-sequencing data from untreated and treated NB samples. These transcriptomic datasets were used to support protein-level findings and to identify prognostic gene signatures. Results B-cell infiltration in NB tumors strongly correlated with the presence of T cells and DCs at both protein and transcriptomic levels, and was associated with improved prognosis. Similar to other solid tumors, B cells in NB were either scattered throughout the tumor or organized into TLSs of varying maturity. Spatial proteomic and transcriptomic analyses revealed that localized tumors often contain mature TLSs, with functional B cells able to antigen presentation and immunoglobulin expression, alongside high cytotoxic T cells. In contrast, metastatic tumors primarily exhibited immature TLSs, with evidence of B-cell and T-cell dysfunction. Importantly, we identified gene signatures associated with B cells and TLSs that not only predicted survival in NB but were also prognostic in multiple adult cancers. Conclusions Our findings highlight a central role for B cells and TLSs in shaping the immune microenvironment of NB. Their presence and maturation status are linked to clinical outcome, suggesting their potential as prognostic biomarkers and targets for novel immunotherapeutic strategies in pediatric oncology.

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