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Identification of marginal zone B cells in head and neck cancer with immunomodulatory characteristics.

Jiantong Bao·Jochen Hess·Annika C Betzler·Zhen Zhang·Miltiadis Tsesmelis·Sebastian Schmid·Gaurav Berry·Patrick J Schuler·Jens Greve·Simon Laban·Thomas K Hoffmann·Medhanie Mulaw·Cornelia Brunner
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Abstract

INTRODUCTION: Recently we observed high numbers of marginal zone B cells (MZBs) within murine head and neck squamous cell carcinoma (HNSCC) with immunosuppressive potential. To date, MZBs have not been linked to tumor development or tumor prevention. OBJECTIVES: Based on our previous findings the present study aimed to validate the presence of MZB in HNSCC and to investigate their possible implications in tumorigenesis and prognosis. METHODS: Flow cytometry was used to uncover MZB within tumors and blood of HNSCC patients. A single-cell RNA sequencing cohort of 118 HNSCC patients across different disease stages and 6 healthy donors (HDs) was compiled. Comparative transcriptomic profiling of B lymphocytes between HNSCC and HDs were performed. Downstream analysis, such as pathway enrichment, cell-cell communication, pseudotime trajectory inference, survival correlation, and spatial transcriptomics were applied. RESULTS: Two MZB subsets were revealed in tissues and blood of HNSCC patients and HDs. The tumor-associated MZBs were featured with hypoxia stress and viral-related hallmark genes. MZB-2, characterized by elevated expression of activation markers and immune-regulatory genes, displayed strong interactions with CD4+ T cells and antigen-presenting cells. These interactions were supported by costimulatory signals in HDs but were absent in HNSCC patients. Co-localization of MZB-2, germinal center B cell (GCB), and CD4+ follicular helper T cell (Tfh) was detected in HNSCC, suggesting the presence of an intratumoral MZB-Tfh-GCB axis. Clinically, MZB-2 abundance was associated with favorable prognosis in early-stage HNSCC, but not in advanced disease. Immunosuppressive gene signatures were not exclusive to MZBs, indicating that they do not represent a purely regulatory B cell phenotype. CONCLUSION: Our findings demonstrate an immunomodulatory role of MZBs in tumor immunity, balancing antigen presentation, cytokine signaling, and immune suppression. The association of MZB-2 with improved prognosis in early-stage HNSCC highlights its potential as a beneficial regulator of antitumor immunity during early tumor progression.

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HumansHead and Neck NeoplasmsB-LymphocytesFemaleMalePrognosisImmunomodulationSquamous Cell Carcinoma of Head and NeckGene Expression ProfilingMiddle AgedAntigen presentationHead and neck squamous cell carcinomaMZB-Tfh-GCB axisMarginal zone B cellsJournal ArticleResearch Support, Non-U.S. Gov't

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Jiantong Bao, Jochen Hess, Annika C Betzler, Zhen Zhang, Miltiadis Tsesmelis, Sebastian Schmid, Gaurav Berry, Patrick J Schuler, Jens Greve, Simon Laban, Thomas K Hoffmann, Medhanie Mulaw, Cornelia Brunner. 2025-11-29. Identification of marginal zone B cells in head and neck cancer with immunomodulatory characteristics.. https://doi.org/10.1016/j.jare.2025.11.070

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