Site-specific Hyper-phosphorylation of IRF2BP2 Modulates Tumor PD-L1 Expression in Medulloblastoma

Background

My project is to determine why hyper-phosphorylation of IRF2BP2 in the absence of Cdk5 prolongs the IRF2BP2 protein half-life. This leads to reduced ability of the tumor cells to up-regulate immune checkpoint molecule PDL1 (programmed death ligand 1) during immune attack. PD-L1 is a cell surface molecule produced by tumor cells that tells T cells that it is part of the person's body so the immune system ignores it. Interferon-gamma enhances the expression of PD-L1 on tumor cells, allowing the tumor cells to resist immune attack.

I will help produce site-directed mutagenesis of serine-440 and serine-443. The purpose of creating the mutagenesis is to change the serine into alanine, a different amino acid that cannot be phosphorylated. Hyper-phosphorylation of the two serine residues on IRF2BP2 prolong its half-life. It is still unknown why this happens, therefore we are researching that cause. I will correlate my findings of IRF2BP2 protein stability to the amount of PD-L1 that is expressed by tumor cells when they are exposed to interferon-gamma.

Project Goal

Ultimately, the goal of my project is to develop an approach to block Cdk5 function in tumors in order to increase the immune system's ability to kill the cancer cell. This study will be performed in a mouse model of Medulloblastoma, the most common malignant brain tumor of childhood.