Expression of H_v1 proton channels in myeloid-derived suppressor cells (MDSC) and its potential role in T cell regulation

Abstract

Significance Immunosuppression by myeloid-derived suppressor cells (MDSC), especially near tumor surfaces, involves the extracellular production of reactive oxygen species (ROS). ROS generation in MDSC occurs during the oxidation of NADPH to NADP+, which NOX2 catalyzes. ROS react with the T cell receptor complex, abolishing the antigen presentation, which blocks the immune system elimination of the tumor cells. Extrusion of protons from MDSC by voltage-gated proton channel (H v 1) sustains ROS production. Here, we demonstrate the expression of H v 1 in mouse MDSC. In this way, H v 1 present in MDSC becomes a potential cancer therapeutic target since its inhibition seems to diminish immunosuppression activity in the tumoral microenvironment, allowing cancer cells to be attacked by the immune system.

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

“…Our study, for the first time, detected within a tumor a high number of Hv1 + myeloid cells that are consistent with the cell surface maker phenotype of PMN- and Mo-MDSCs (see above). Our electrophysiology results are consistent with the data described for in vitro produced MDSCs where Hv1 H + currents of similar magnitude (between 200 pA and 1 nA at +130 mV) to our study were reported using patch-clamp in a mixed MDSC population [ 21 ]. The MDSCs used by Alvear-Arias et al were obtained by induction of the differentiation of bone marrow-derived myeloid precursors by GM-CSF [ 21 ] whereas in our study, MDSCs were isolated directly from LLC tumors induced in mice.…”

“…Second, the whole-cell currents in both MDSC types were sensitive to the pH gradient across the membrane and the membrane potential. The threshold voltage for the activation of the currents shifts along the voltage axis when changing ΔpH, ~40 mV per unit change in the extracellular pH, closely mirroring what has already been described for proton currents in various cells [ 43 , 62 ] including bone-marrow-derived MDSCs [ 21 ]. On the other hand, V thr of the current varies among different cell types [ 42 , 63 ].…”

“…A recent study reported the expression of the voltage-gated proton channel Hv1 in in vitro differentiated MDSCs [ 21 ]. Motivated by this, we tested the expression of the Hv1 transcript in PMN- and Mo-MDSCs isolated from the LLC tumor using qPCR ( Figure 5 ).…”

“…ClGBI is an apolar small molecule, which can cross the plasma membrane and block the Hv1 channel from the cytosolic side [ 44 ]. The sensitivity to guanidine derivatives, and particularly to ClGBI, is often used in the literature as a pharmacological argument for the identification of Hv1 currents [ 21 , 34 , 42 , 45 ]. Accordingly, we tested the sensitivity of the whole-cell currents to ClGBI at 200 µM concentration, which was reported to block ~80% of the Hv1 current in a reversible manner [ 44 ].…”

“…TRPV1 activation with cannabidiol stimulates the recruitment and activation of MDSCs and this exerts a protective function in a murine hepatitis model [ 20 ]. Very recently, the functional expression of the Hv1 proton channel was described in in vitro differentiated murine MDSCs [ 21 ].…”