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 the ecrg4 null glioma-initiating cell (GIC) line, which was generated from neural stem cells of ecrg4 knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted ecrg4 wild type-GIC line GIC(C/C) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4 C , CD8 C , or NK cells by specific antibodies in vivo recovered tumorigenicity of GIC(C/C). 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 in vitro. Moreover, blockades of type-I interferon (IFN) signaling in vivo, either depleting IFN-a/b receptor 1 or using stat1 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.

Ecrg4 deficiency extends the replicative capacity of neural stem cells in a Foxg1-dependent manner

“…Proliferation of Ecrg4 −/− cells significantly decreased when cultured with Ecrg4 +/+ cells (this study). Ecrg4 has been shown to induce the expression of pro-inflammatory factors, which are involved in the initiation and maintenance of cell senescence in microglia/macrophages through the activation of scavenger receptor/NF-κB signaling pathway (Kizil et al, 2015;Moriguchi et al, 2016Moriguchi et al, , 2018. Furthermore, we have demonstrated here that Ecrg4 deficiency increased spatial learning and memory in mice.…”

“…We investigated the molecular mechanism of how Ecrg4 deficiency keeps NSC proliferation. Ecrg4 was shown to induce the expression of pro-inflammatory cytokines, which prevent NSC proliferation, through the activation of a scavenger receptor/NF-κB signaling pathway in microglia (Lee et al, 2015;Kizil et al, 2015;Moriguchi et al, 2016Moriguchi et al, , 2018. As cultured NSCs express both Ecrg4 and potential Ecrg4 receptors, including CD36 and Scarf1 ( Fig.…”

“…Decreases in Ecrg4 expression were subsequently detected in various types of cancer tissues (Götze et al, 2009;Sabatier et al, 2011;Yue et al, 2003). While overexpression of Ecrg4 was found to prevent tumorigenesis by inhibiting cancer cell proliferation, it was revealed that Ecrg4 fragments secreted from cancer cells induced tumor eradication by activating both innate and adaptive immune system in vivo (Li et al, 2009(Li et al, , 2010Moriguchi et al, 2016;Xu et al, 2013). Taken together, these findings indicated that Ecrg4 acts as a novel type of tumor suppresser.…”

Collateral Damage: What Effect Does Anti-CD4 and Anti-CD8α Antibody–Mediated Depletion Have on Leukocyte Populations?

“…Two hundred and nine publications used an in vivo approach to deplete CD4 + cells in a mouse model, of which 145 used anti-CD4 Ab injection regimens. Of these, 137 manuscripts attempted to deplete CD4 + T cells only, whereas just seven manuscripts acknowledged that any CD4 + cells could have been affected by this methodology (26)(27)(28)(29)(30)(31)(32). More than 80% of all published work performing anti-CD4 Ab-mediated depletion method used GK1.5.…”

“…Similarly, of the 809 manuscripts found on CD8 depletion, 801 manuscripts had English full texts available, and 185 papers performed anti-CD8 Ab-mediated depletion of CD8 + cells in vivo. Six articles stated that any CD8-expressing cells could have been affected (27,29,30,(33)(34)(35), whereas 178 papers did not comment on cells other than T cells. Diverse clones of anti-CD8a and anti-CD8b Abs were used, with anti-CD8a Ab clones 2.43 and 53-6.7 being the most common choices (Fig.…”