BRIEF RESEARCH REPORT article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Exploratory Spatial Transcriptomic Profiling of Peritumoral Th2 Immune Polarization in HPV-Positive Oropharyngeal Cancer
Provisionally accepted
Naohiro Wakisaka*
Makiko Moriyama-Kita
Satoru KondoEiji KobayashiTakayoshi UenoYosuke NakanishiKazuhira EndoHisashi Sugimoto
Tomokazu Yoshizaki- Kanazawa University, Kanazawa, Japan
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Introduction: Oropharyngeal squamous cell carcinoma (OPC) associated with high-risk human papillomavirus (HPV), particularly HPV-16, generally shows favorable outcomes yet paradoxically exhibits a high incidence of early lymphatic metastasis. The immune mechanisms underlying this phenomenon remain unclear. Methods: We conducted an exploratory spatial transcriptomic analysis using the GeoMx Digital Spatial Profiler on formalin-fixed, paraffin-embedded samples from six patients with palatine tonsil-derived OPC. Tumor tissue regions (TTRs) and lymphoid follicular regions (LFRs) were compared according to HPV status and nodal involvement. Results: In HPV-positive LFRs, pathways related to B-cell apoptosis appeared downregulated, suggesting prolonged B-cell survival and antigen presentation. Metastasis-negative HPV-positive cases displayed a Th2-skewed immune profile in LFRs, with increased naïve B cells, plasma cells, eosinophils, M2 macrophages, and activated mast cells. In contrast, metastasis-positive cases showed increased T cell activation in LFRs and reduced proliferation-related signaling in TTRs. Pathways involving estrogen signaling and bile acid metabolism were also associated with metastatic behavior. Conclusion: These exploratory findings suggest that peritumoral Th2-biased immunity within lymphoid structures may contribute to restraining lymphatic metastasis in HPV-positive OPC. Spatial transcriptomics may provide a high-resolution framework for investigating tumor–immune interactions and generating hypotheses for future mechanistic and clinical studies.
Keywords: HPV-positive oropharyngeal cancer, Palatine Tonsil, Spatial transcriptomics, Tumor immune microenvironment, Th2 immunity, Lymphatic Metastasis, Eosinophils and mast cells, estrogen signaling
Received: 26 Oct 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 Wakisaka, Moriyama-Kita, Kondo, Kobayashi, Ueno, Nakanishi, Endo, Sugimoto and Yoshizaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Naohiro Wakisaka, wakisaka@med.kanazawa-u.ac.jp
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