title: Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling.
abstract: Esophageal cancer-related gene 4 (Ecrg4), a hormone-like peptide, is thought to be a tumor suppressor, however, little is known about the mechanism of how Ecrg4 suppresses tumorigenesis. Here, we show that theecrg4null glioma-initiating cell (GIC) line, which was generated from neural stem cells ofecrg4knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplantedecrg4wild type-GIC line GIC(+/+) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4+, CD8+, or NK cells by specific antibodiesin vivorecovered tumorigenicity of GIC(+/+). We demonstrate that Ecrg4 fragments, amino acid residues 71-132 and 133-148, which are produced by the proteolitic cleavage, induced the expression of pro-inflammatory cytokines in microgliain vitro. Moreover, blockades of type-I interferon (IFN) signalingin vivo, either depleting IFN-α/β receptor 1 or usingstat1KO mice, abrogated the Ecrg4-dependent antitumor activity. Together, our findings indicate a major antitumor function of Ecrg4 in enhancing host immunity via type-I IFN signaling, and suggest its potential as a clinical candidate for cancer immunotherapy.
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Division of Functional immunology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kaneumi
authors.affiliation: ASUBIO pharma Co.,Ltd. Kobe, Hyogo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takeda
authors.affiliation: ASUBIO pharma Co.,Ltd. Kobe, Hyogo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Enomoto
authors.affiliation: Department of Anti-aging and Genomics, Ehime University Proteo-Medicine Research Center , To-on, Ehime, Japan.
authors.forename: Shyam Kumar
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Department of Anti-aging and Genomics, Ehime University Proteo-Medicine Research Center , To-on, Ehime, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Miki
authors.affiliation: ASUBIO pharma Co.,Ltd. Kobe, Hyogo, Japan.
authors.forename: Uichi
authors.initials: U
authors.lastname: Koshimizu
authors.affiliation: Division of Functional immunology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
keywords: Ecrg4; glioma; immunosurveillance; microglia; type-I IFN