Introduction Cancer immunology often overlooks lymph nodes (LNs), focusing mainly on tumor sites. Our previous research demonstrated that neutrophils in tumor-draining LNs of head and neck cancer (HNC) patients enhance survival by promoting B cell activation. We aim to explore the underlying mechanisms of this interaction.

Materials and Methods We analyzed FFPE samples from 43 HNC patients' tumor-draining LNs, assessing LN morphology with a focus on follicles and germinal centers (GC). Immunohistochemistry targeted B cell activation markers (BLIMP1, IgG3) and neutrophil chemokines (BAFF, APRIL) involved in B cell activation. LN cytokines were analyzed with a multiplex array, and mechanisms are studied in vitro by flow cytometry.

Results Reduced GC formation in metastatic LNs correlated with poor prognosis, suggesting that enhanced B cell activation may improve survival. N0 LNs showed higher B cell-stimulating potential, with increased cytokine expression compared to advanced-stage LNs. A gradient of B cell activation was observed, with the highest BLIMP1 expression in the sinuses and medulla. Spatial analysis revealed neutrophils did not directly influence BLIMP1 in B cells, and BLIMP1 levels were not linked to prognosis, yet HNC-derived factors suppressed BAFF expression in neutrophils, limiting B cell activation.

Discussion In early-stage LNs, elevated cytokines and GC presence are in line with the tertiary lymphatic structures positive HNC prognostic impact. While BLIMP1 expression in B cells did not correlate with immune responses, further investigation into BAFF, APRIL, and IgG3 may clarify the mechanisms of neutrophil-mediated B cell activation in tumor-draining LNs. These findings could guide new therapeutic strategies targeting this immune pathway in HNC.

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