PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy
Menée à l'aide de lignées cellulaires de cancer colorectal, de cancer du sein triple négatif, de mélanome et de tumeur de Lewis puis menée à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel l'inhibiteur des activateurs du plasminogène PAI-1 sécrété par les cellules cancéreuses réduit l'effet abscopal de la radio-immunothérapie en déclenchant la transformation des péricytes tumoraux distants en fibroblastes CAF exprimant fortement la protéine SFRP2
The abscopal effect of radioimmunotherapy, wherein tumor shrinkage occurs beyond the irradiated field, is therapeutically promising but clinically rare. The mechanisms underlying this effect remain elusive. Here, in vivo genome-wide CRISPR screening identifies SFRP2 as a potential stromal regulator of the abscopal effect. SFRP2 exhibits cancer-associated fibroblast (CAF)-specific expression and radioimmunotherapy-mediated upregulation in unirradiated tumors. Conditional Sfrp2 knockout in CAFs boosts the abscopal effect by rewiring the vascular-immune microenvironment to promote CD8+ T cell recruitment to unirradiated tumors. In vivo lineage tracing reveals that elevated SFRP2 correlates with radioimmunotherapy-driven pericyte lineage commitment. Serum proteomics reveals that irradiated-tumor-secreted PAI-1 triggers distant tumor pericyte cell-fate transition into SFRP2high CAFs via the LRP1/p65 axis. Pharmacologically blocking SFRP2 or PAI-1 enhances the abscopal effect in humanized patient-derived xenograft models. Our findings collectively illustrate that PAI-1-induced SFRP2high CAFs serve as critical stromal regulator to hijack the abscopal effect, providing promising targets for enhancing radioimmunotherapy effectiveness.
Cancer Cell , résumé, 2025