CD40 SIGNALING DECREASES MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE (MELK) EXPRESSION AND CORRELATES WITH SURVIVAL IN GLIOBLASTOMA PATIENTS

We previously demonstrated that the high expression levels of CD40/ CD40 ligand (CD40L) correlated with better prognosis in glioblastomas (GBMs). CD40 is a costimulatory molecule and its agonistic antibody, FGK45 has shown to augment antitumor effects of immunotherapy against GL261, glioma cell, and NSCL61, glioma-initiating cell (GIC)-like cell model mice. Studying the mechanism of FGK45 induced anti-tumor effect against glioma models, we identified that the expression of maternal embryonic leucine-zipper kinase (MELK) is down regulated in FGK45 treated mice. MELK is a serine/ threonine kinase involved in cancer cell proliferation and maintenance of stemness. In this study, we evaluated the relationship between CD40 signaling and MELK expression in gliomas. We tested the MELK expression in NSCL61, and Lewis lung carcinoma (LLC) cell model mice treated with FGK45 immunotherapy. Subsequently, we analyzed direct effects of FGK45 against GL261, NSCL61, and LLC in vitro. Then, we assessed the expression of MELK and CD40/ CD40L in GBMs and analyzed the correlation with prognosis. Significant decrease of MELK expressions were found in FGK45 treated tumor model mice. In vitro, FGK45 directly decreased MELK expression in glioma cells. In clinical samples, the higher expression levels of MELK mRNA were associated with poor prognosis in GBMs. Moreover, the expression levels of MELK were inversely correlated with CD40/ CD40L expression. In this study, we demonstrated that CD40 signaling decreases the MELK expression in glioma cells. The high expression of CD40/CD40L was inversely correlated with MELK expression and correlated with better prognosis. Immunotherapy using CD40 agonistic antibody reduces MELK expression and can be promising GIC targeting therapy.