ArticleFrontiers in immunology2026
Spatial immune programs associated with nodal status differ between lymphoid follicular regions and peritumoral tonsillar tissue in HPV-positive oropharyngeal cancer.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: In human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), lymph node metastasis is common, yet its biological and prognostic implications remain incompletely understood. Less is known about the spatial organization of immune programs within tumor-associated secondary lymphoid structures. Methods: Immune programs were analyzed by spatially distinguishing lymphoid follicular regions (LFRs) from tumor-free peritumoral tonsillar tissues (PTTs) in palatine tonsil-derived HPV-positive OPC. LFRs were analyzed using spatial transcriptomics and PTTs using bulk transcriptomics. Previously generated GeoMx Digital Spatial Profiler and bulk microarray datasets were reanalyzed to investigate compartment-specific immune programs. Immune pathway activity was assessed using single-sample gene set enrichment analysis according to nodal status. Results: Compartment-specific immune programs associated with nodal status were identified in both LFRs and PTTs. In LFRs, nodal-positive cases showed enrichment of stem-like, pre-exhausted, and T-cell activity programs accompanied by inflammatory and interferon-associated signaling. In contrast, nodal-negative PTTs exhibited enrichment of stem-like, pre-exhausted, and T-cell activity programs together with IL2-STAT5 and TGF-β signaling, without overt inflammatory activation. These findings indicate that identical immune pathways exhibit distinct biological associations depending on their spatial localization. Conclusion: Immune programs associated with nodal metastasis in HPV-positive OPC vary according to spatial immune context. Distinguishing LFRs from tumor-free PTTs provides a framework for interpreting immune programs beyond bulk tissue analysis and highlights the importance of spatial immune organization in shaping biological interpretation. Because the spatial transcriptomic analyses were performed in a limited number of patients, these findings should be considered exploratory and require validation in larger independent cohorts.
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