ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
The local cellular response to Human Papillomavirus focuses on basal layer restoration as visualized in situ by specific cellular neighborhoods near infected cells
Provisionally accepted
Roderick Slieker
Ziena Abdulrahman
Saskia J SantegoetsMariette I E van Poelgeest
Marij J.P. Welters
Sjoerd H Van Der Burg*- Leiden University Medical Center (LUMC), Leiden, Netherlands
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Background Human papillomavirus type 16 (HPV16) is known to deregulate and cause hyperproliferation of the infected epithelium, but its full effect on the host's tissue has remained elusive as earlier comprehensive studies were restricted to in vitro models. Aim The aim of the current study was to study HPV16-induced tissue changes in vulvar tissue in its full natural context by using single-cell spatial transcriptomics. Methods We applied spatial single-cell spatial transcriptomics to formalin-fixed paraffin-embedded healthy vulvar tissue (n=5) and HPV16+ high grade vulvar lesions (vHSIL, n=31). Results More than 415,000 individual cells were identified and annotated in situ, to create complete digital atlases of the healthy vulvar and HPV16+ vHSIL tissues for comparison. Two subpopulations of basal cells were identified, one of which lined the basal membrane of healthy tissue, the other is characterized by a transcriptomic signature like HPV16-infected keratinocytes and upregulated inflammatory genes and observed predominantly in vHSIL. Epithelial cells in the parabasal layers of vHSIL upregulated the expression of genes associated with inflammation and proliferation. Importantly, HPV16 profoundly remodeled stromal fibroblasts, endothelial, and immune cells, reorganizing them into distinct cellular neighborhoods of which three dominated vHSIL. A regenerative niche adjacent to the basal layer, a perilesional niche characterized by immune suppression, and a more distal niche enriched for adaptive immune activity. Conclusion In conclusion, spatial analysis reveals that HPV16 infection orchestrates a coordinated tissue response, driving basal layer restoration while locally suppressing immune activation to prevent pathological damage.
Keywords: CosMx, Spatial transcriptomics, VIN, vHSIL, neighborhoods
Received: 20 Oct 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Slieker, Abdulrahman, Santegoets, van Poelgeest, Welters and Van Der Burg. 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: Sjoerd H Van Der Burg, s.h.van_der_burg@lumc.nl
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