High-dimensional imaging of the HPV-induced tumor microenvironment to improve clinical outcomes

Abdulrahman, Z. (2026)

Doctoral Thesis

This thesis investigates how the tumor microenvironment shapes immunotherapy response and survival in patients with HPV-induced (pre)cancers. Leveraging state-of-the-art spatial imaging and single-cell technologies, it demonstrates that effective anti-tumor immunity is driven not merely by immune cell abundance, but by the functional and spatial organization of immune cells within the tissue.
 

Across HPV-induced precancers of the cervix and vulva, clinical response to immunotherapy was consistently associated with the presence of a pre-existing coordinated inflammatory microenvironment, whereas immunologically cold lesions remained largely resistant to immunotherapy. Spatial transcriptomic analyses revealed that responders harbor distinct immune-supportive spatial ecosystems that are absent in non-responders.
 

In HPV-induced vulvar and head and neck cancers, prolonged survival was strongly linked to the presence of organized intratumoral immune microaggregates that enable interactions between T cells and antigen-presenting cells, sustaining effective local anti-tumor immunity.
 

Collectively, these findings identify that the spatial immune architecture of a tumor is a fundamental determinant of therapeutic efficacy and patient outcome. This work advances a conceptual shift in cancer immunology, from quantifying immune cell populations to understanding tumors as spatially organized ecosystems, and provides a framework for the development of next-generation biomarkers and personalized immunotherapeutic strategies.

• Immunotherapy
• Tumor microenvironment
• Biomarkers
• Personalized therapy
• Clinical outcomes
• HPV-induced (pre)cancers
• Spatial ecosystems
• Anti-tumor immunity

• All authors: Abdulrahman, Z.
• Supervisor: Burg, S.H. van der; Miranda, N.F.C.C. de
• Co-supervisor: Poelgeest, M.I.E. van
• Committee: Kroep, J.R.; Arens, R.; Gruijl, T.D. de; Debets, R.J.E.M.A.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2026-09-03
• ISBN (print): 9789465377285