Potentiation of immune checkpoint blockade with a pH-sensitizer as monitored in two pre-clinical tumor models with acidoCEST MRI.

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.