Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling.

Esophageal cancer-related gene 4 (), 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 the null glioma-initiating cell (GIC) line, which was generated from neural stem cells of knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted wild 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 antibodies recovered 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 microglia . Moreover, blockades of type-I interferon (IFN) signaling , either depleting IFN-α/β receptor 1 or using KO 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.