Abstract P80: Unveiling Precision Targets of PD-1 Blockade Hyperprogression in Cervical Adenocarcinoma via Longitudinal Single-Cell and Spatial Monitoring

Abstract

Cervical adenocarcinoma, a significant subtype of cervical cancer, exhibits variable responses to immune checkpoint inhibitors, with some patients experiencing hyperprogressive disease (HPD) characterized by accelerated tumour progression. The molecular and cellular mechanisms underlying HPD remain poorly understood. In this study, we employed single-cell RNA sequencing, T cell receptor profiling, and spatial transcriptomics to longitudinally analyse the tumour and its microenvironment of a cervical adenocarcinoma patient who developed HPD following anti-PD-1 immunotherapy. Our integrated analyses revealed two key mechanisms driving HPD: LAG3-mediated immune evasion driven by the IFNγ-STAT1 axis in T/NK cells, and fibroblast-dependent epithelial proliferation and survival via IGF1-IGF1R signalling. Additionally, spatial transcriptomics identified the formation of a distinct metastatic niche post-immunotherapy. These findings nominate LAG3 and IGF1R as actionable therapeutic targets and demonstrate the power of real-time, multi-modal profiling to identify adaptive hyperprogression mechanisms. Our work underscores the importance of longitudinal monitoring in precision oncology and provides a framework for developing personalized interventions for minimal residual disease, non-responders, and HPD.