The Voltage-Gated Hv1 H+ Channel Is Expressed in Tumor-Infiltrating Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are key determinants of the immunosuppressive microenvironment in tumors. As ion channels play key roles in the physiology/pathophysiology of immune cells, we aimed at studying the ion channel repertoire in tumor-derived polymorphonuclear (PMN-MDSC) and monocytic (Mo-MDSC) MDSCs. Subcutaneous tumors in mice were induced by the Lewis lung carcinoma cell line (LLC). The presence of PMN-MDSC (CD11b(+)/Ly6G(+)) and Mo-MDSCs (CD11b(+)/Ly6C(+)) in the tumor tissue was confirmed using immunofluorescence microscopy and cells were identified as CD11b(+)/Ly6G(+) PMN-MDSCs and CD11b(+)/Ly6C(+)/F4/80(-)/MHCII- Mo-MDSCs using flow cytometry and sorting. The majority of the myeloid cells infiltrating the LLC tumors were PMN-MDSC (similar to 60%) as compared to similar to 10% being Mo-MDSCs. We showed that PMN- and Mo-MDSCs express the Hv1 H+ channel both at the mRNA and at the protein level and that the biophysical and pharmacological properties of the whole-cell currents recapitulate the hallmarks of Hv1 currents: similar to 40 mV shift in the activation threshold of the current per unit change in the extracellular pH, high H+ selectivity, and sensitivity to the Hv1 inhibitor ClGBI. As MDSCs exert immunosuppression mainly by producing reactive oxygen species which is coupled to Hv1-mediated H+ currents, Hv1 might be an attractive target for inhibition of MDSCs in tumors.

Automated summary

Myeloid-derived suppressor cells (MDSCs) play a key role in the immunosuppressive microenvironment of tumors. This study investigated the ion channel repertoire in tumor-derived PMN-MDSC and Mo-MDSCs, and found that Hv1 H+ channel is expressed in both types of MDSCs. Hv1 might be a potential target for inhibiting MDSCs in tumors.