Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma

Zheng, J.; Wang, L.; Zhao, S.; Ayasoufi, K.; Goddery, E. N.; Strege, P. R.; Wan, Y.; Zhang, W.; Xie, M.; Beyder, A.; Johnson, A.; Wu, L.-J.

doi:10.1101/2024.10.18.619142

bioRxiv · 10.1101/2024.10.18.619142

Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma

Zheng, J.·Wang, L.·Zhao, S.·Ayasoufi, K.·Goddery, E. N.·Strege, P. R.·Wan, Y.·Zhang, W.·Xie, M.·Beyder, A.·Johnson, A.·Wu, L.-J.

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Abstract

In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword--they are a major cellular component modulating the immune response while presenting a potential therapeutic target. Our study highlights the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a crucial regulator of their physiological functions. We discovered a strong correlation between increased Hv1 expression and poor prognosis in glioblastoma patients. Depleting Hv1 significantly extended survival in a mouse model of glioma. Employing multiple novel transgenic mouse lines, we demonstrated that Hv1 is upregulated in response to tumor presence, with glioma-associated macrophages as the principal contributors. Specifically, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a combination of in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we found that Hv1 depletion leads to reduced macrophage infiltration and enhanced antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma.

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Zheng, J., Wang, L., Zhao, S., Ayasoufi, K., Goddery, E. N., Strege, P. R., Wan, Y., Zhang, W., Xie, M., Beyder, A., Johnson, A., Wu, L.-J.. 2024-10-22. Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma. https://doi.org/10.1101/2024.10.18.619142

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