Dendritic Cells Require TMEM176A/B Ion Channels for Optimal MHC Class II Antigen Presentation to Naive CD4+ T Cells

Abstract

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TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer

“…Previously reported to be an ion channel on endo-phagosomes that regulates their pH, the main focus of research on TMEM176B has related to its expression on immune cells and its immunoregulatory effects [ 4 , 6 , 7 , 10 , 12 ]. Studies examining the importance of TMEM176B expression in cancer cells have been limited, and reports on its intracellular localization in different cells have been conflicting [ 4 , 9 ].…”

“…The AKT/mTOR signaling pathway is known to be an important mediator of cancer progression, and its activation is associated with unfavorable outcomes [ 63 , 64 ]. As AKT signaling can be influenced by protein recycling, which is regulated by endosomes, and as TMEM176B is a putative cation channel that has been reported to regulate the pH of endosomes, it is possible that silencing TMEM176B alters cell signaling by affecting protein recycling [ 4 , 6 , 19 ]. However, it remains to be determined whether our observed effects of TMEM176B overexpression and silencing on AKT/mTOR signaling were directly related to TMEM176B expression, or indirectly through the altered expression of MAGEA6, PBX1 , or GABRA3 .…”

“…Although TMEM176B was described in human lung fibroblasts more than 20 years ago [ 3 , 4 ], the understanding of its role in cancer biology remains limited. Previous studies have described TMEM176B as an acid-sensitive cation channel, and research has primarily focused on its role in immune cell regulation [ 4 , 5 , 6 ]. Myeloid lineage immune cells express TMEM176B, in which it regulates dendritic cell maturation and antigen presentation [ 6 , 7 ].…”

“…Previous studies have described TMEM176B as an acid-sensitive cation channel, and research has primarily focused on its role in immune cell regulation [ 4 , 5 , 6 ]. Myeloid lineage immune cells express TMEM176B, in which it regulates dendritic cell maturation and antigen presentation [ 6 , 7 ]. Higher TMEM176B expression has been found in immature dendritic cells in allograft tolerance models and in patients with spinal cord injuries [ 8 , 9 ], while lower expression has been reported in mature dendritic cells.…”

“…In dendritic cells, TMEM176B was reported to contribute to their suppressive function by permitting the sodium counterflux required for the acidification of endophagosomes [ 4 ]. It has additionally been reported to traffic through the Golgi apparatus in TMEM176B transfected HeLa cells, although there are conflicting results regarding its subcellular localization in different cell types [ 4 , 5 , 6 , 10 ]. The whole-body deletion or pharmacological inhibition of TMEM176B in murine cancer models decreased tumor growth through enhanced anti-tumor T cell immunity and improved the response to immune checkpoint inhibitors [ 4 , 10 ].…”