Abstract
Proton pump inhibitors have been explored for potentiating cancer therapies via reverting the tumor acidity and promoting the activation of anti-tumor immune responses. To regulate the intracellular pH of melanoma and immunosuppressive myeloid cells, we developed poly(L-lactide-co-glycolide) nanoparticles loaded with esomeprazole (ESO-NPs). The effect of ESO-NPs on melanoma cells was observed as alkalinization and reduction of melanin content accompanied by a decrease of microphthalmia-associated transcription factor (MITF), poliovirus receptor (PVR), and programmed death ligand 1 (PD-L1) immune checkpoint expression. ESO-NP treatment of melanoma-patient-derived and in vitro-induced myeloid-derived suppressor cells (MDSCs) reduced the expression of immunosuppression-associated molecules PD-L1, CD206, and CD163 on patient-derived myeloid cells while inducing the expression of co-stimulatory molecule CD86 and HLA-DR in the in vitro model. Our findings suggest that reprogramming the intracellular pH of melanoma and immune-suppression-associated myeloid cells with ESO-NPs can modulate the expression of proteins involved in resistance to cancer therapy and immunosuppression, thus potentially improving the response to immunotherapies.