Potentiation of immune checkpoint blockade with a pH-sensitizer as monitored in two pre-clinical tumor models with acidoCEST MRI
Menée à l'aide de deux modèles tumoraux, cette étude met en évidence l'intérêt de sensibilisateurs au pH pour améliorer le contrôle de la tumeur par inhibiteurs de point de contrôle immunitaire et démontre la possibilité d'utiliser l'IRM acidoCEST pour mesurer le pH extracellulaire des tumeurs et prédire le contrôle tumoral
Background : Tumor acidosis causes resistance to immune checkpoint blockade (ICB). We hypothesized that a “pH-sensitizer” can increase tumor extracellular pH (pHe) and improve tumor control following ICB. We also hypothesized that pHe measured with acidoCEST MRI can predict improved tumor control with ICB.
Methods : We tested the effects of pH-sensitizers on proton efflux rate (PER), cytotoxicity, T cell activation, tumor immunogenicity, tumor growth and survival using 4T1 and B16-F10 tumor cells. We measured in vivo tumor pHe of 4T1 and B16-F10 models with acidoCEST MRI.
Results : Among the pH-sensitizers tested, someprazole caused the greatest reduction in PER without exhibiting cytotoxicity or reducing T cell activation. Esomeprazole improved 4T1 tumor control with ICB administered one day after the pH-sensitizer. Tumor pHe positively correlated with TCF-1 + CD4 effector and CD8 T cell intratumoral frequencies and predicted improved 4T1 tumor control with ICB. For comparison, esomeprazole had a mild effect on B16-F10 tumor pHe, and worsened tumor control with ICB and increased intratumoral myeloid and dendritic cell (DC) frequencies.
Conclusions : A pH-sensitizer can improve tumor control with ICB, and acidoCEST MRI can be used to measure pHe and predict tumor control, but only in the 4T1 model and not the B16-F10 model.
British Journal of Cancer , résumé, 2025