TMIC-09. HV1 PROTON CHANNELS PROMOTE MYELOID INFILTRATION AND GLIOMA PROGRESSION. (14th November 2022) - Zheng, Jiaying
Abstract: Myeloid cells comprising up to 50% of total tumor mass in glioblastoma (GBM) contribute to tumor progression and immunosuppression. Restraining glioma-induced myeloid cell infiltration increases functional T cells within the tumors, improves the efficacy of checkpoint blockade, and significantly extends mouse survival. Here, we focus on an ion channel, voltage-gated proton channel Hv1, which is mainly expressed in myeloid cells and shapes the physiological functions of myeloid cells. Our bioinformatics analysis demonstrated that elevated Hv1 expression in the tumor mass correlates with poor disease prognosis in patients. Using the leading immunocompetent model of GBM in mice, we showed that Hv1 knockout mice (Hv1 -/- ) exhibit slower glioma progression and prolonged survival. Notably, in vivo two-photon imaging, immunofluorescence, and full-spectrum flow cytometry revealed that Hv1 -/- mice have reduced monocyte/macrophage infiltration, higher frequency of MHCII + among all infiltrating myeloid cells, and increased PD-1 + CD4 + T cells in the tumor-burdened hemisphere. As a result, we combined anti-PD-1 treatment with Hv1 knockout in the middle stage of glioma, and found that approximately 30% of Hv1 -/- mice were cured. Together, our results demonstrated that Hv1 regulates myeloid infiltration and could be a novel therapeutic target for the treatment of GBM.