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

Abstract

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.