Loss of voltage-gated hydrogen channel 1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T cells

Coe, David; Poobalasingam, Thanushiyan; Fu, Hongmei; Bonacina, Fabrizia; Wang, Guosu; Morales, Valle; Moregola, A.; Mitro, Nico; Cheung, Katherine; Ward, Emily M. Geraghty; Nadkarni, Suchita; Aksentijević, Dunja; Bianchi, Katiuscia; Norata, Giuseppe Danilo; Capasso, Melania; Marelli‐Berg, Federica M.

doi:10.1172/jci.insight.147814

Cited by 7 publications

(12 citation statements)

References 46 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, modulating the acidic tumor microenvironment by Hv1 inhibition may facilitate the tumor-suppressive effect of immune cells in cancer therapy. However, recently it has also been shown that the increase of intracellular acidity in activated T cells due to the lack of Hv1 proton channel reduces the effector function of T cells [ 31 ], which must also be considered to determine the overall outcome of Hv1-targeted cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Hv1 is activated, among others, by membrane depolarization, the pH gradient across the plasma membrane and temperature [ 23 ]. The Hv1 proton channel has been described in inflammatory cells such as granulocytes [ 24 , 25 ] macrophages [ 26 ], eosinophils [ 27 ], B cells [ 28 ], plasmacytoid DCs [ 29 ] and to a less extent, in T cells [ 30 , 31 ]. The Hv1 proton channel has been shown to regulate intracellular pH of tumor cells by mediating outward H + fluxes, thereby contributing to the acidification of the TME and the enhanced survival and mobility of tumor cells [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Cozzolino

Gyöngyösi

Korpos

et al. 2023

IJMS

View full text Add to dashboard Cite

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 (~60%) as compared 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: ~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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cozzolino

Gyöngyösi

Korpos

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…The authors conclude that although there is a link between a high number of activated T cells and auto-immunity disease, there is still a need for further evidence in order to confirm if the lack of Hv1 channels is the main inductor of autoimmunity. Recently, the presence of Hv1 channels in T lymphocytes, and that loss of Hv1 in T lymphocytes leads to a metabolic reprogramming and an impaired activation of T lymphocytes that could affect their priming stage, possibly affecting their anti-tumor response ( Coe et al, 2022 ). They evidenced that 200 μM of ClGBI diminished CD8 + T cells pH i , viability and incremented apoptosis and necrosis, but haven’t investigate their anti-tumoral function in these cell types up to date.…”

Section: Hv1 Channel As a Novel And Promising Therapeutic Target In T...mentioning

confidence: 99%

“…The previous experiment does suggest that the addition of ClGBI could alter the number of viable T lymphocytes. Although there is still a need for anti-tumoral response studies regarding inhibition or deletion of Hv1 in these cells, it appears that the inhibition of Hv1 in the tumoral system with ClGBI could affect the anti-tumoral response of T lymphocytes ( Coe et al, 2022 ). On the other hand, there is no evidence regarding inhibition of Hv1 channels in T lymphocytes with zinc ion.…”

Section: Hv1 Channel As a Novel And Promising Therapeutic Target In T...mentioning

confidence: 99%

Role of voltage-gated proton channel (Hv1) in cancer biology

et al. 2023

View full text Add to dashboard Cite

The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.

show abstract

“…Pretreatment of MDSCs with ClGBI reduced their suppressive effect on T cell proliferation, suggesting the potential therapeutic use of H V 1 inhibitors in immunoregulation. However, the presence and possible functional roles of voltage-gated proton currents have also been described in Jurkat T cells, as well as murine and human peripheral T cells [ 23 ] and recently in activated T cells [ 24 ]. Thus, the application of ClGBI in the presence of both MDSCs and T cells may also directly affect the function of the latter cell type, as well.…”

Section: Introductionmentioning

confidence: 99%

5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel

et al. 2023

View full text Add to dashboard Cite

5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H+) channel (HV1, Kd ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive study of its ion channel selectivity determined by electrophysiological methods has not been published yet. The lack of selectivity may lead to incorrect conclusions regarding the role of hHv1 in physiological or pathophysiological responses in vitro and in vivo. We have found that ClGBI inhibits the proliferation of lymphocytes, which absolutely requires the functioning of the KV1.3 channel. We, therefore, tested ClGBI directly on hKV1.3 using a whole-cell patch clamp and found an inhibitory effect similar in magnitude to that seen on hHV1 (Kd ≈ 72 μM). We then further investigated ClGBI selectivity on the hKV1.1, hKV1.4-IR, hKV1.5, hKV10.1, hKV11.1, hKCa3.1, hNaV1.4, and hNaV1.5 channels. Our results show that, besides HV1 and KV1.3, all other off-target channels were inhibited by ClGBI, with Kd values ranging from 12 to 894 μM. Based on our comprehensive data, ClGBI has to be considered a non-selective hHV1 inhibitor; thus, experiments aiming at elucidating the significance of these channels in physiological responses have to be carefully evaluated.

show abstract

Loss of voltage-gated hydrogen channel 1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T cells

Cited by 7 publications

References 46 publications

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

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

Role of voltage-gated proton channel (Hv1) in cancer biology

5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel

Contact Info

Product

Resources

About