The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB

Abstract

Expression of the stress-induced ligands MICA, MICB and ULBP 1–6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines. We also discovered that IMP3 indirectly targets MICB with a mechanism functionally distinct from that of ULBP2. Importantly, IMP3-mediated regulation of stress-ligands leads to impaired NK cell recognition of transformed cells. Our findings shed new light on the regulation of NKG2D ligands and on the mechanism of action of a powerful oncogenic RBP, IMP3.Tumor cells differ from healthy cells in many aspects. Importantly, tumor cells have the ability to divide and grow much faster than normal cells. To protect ourselves from full-grown cancers, our bodies have developed a surveillance system: when a tumor cell starts to divide without restraint, “stress-induced” proteins start to appear on its surface. These proteins help the immune system recognize abnormal or damaged cells, allowing the immune cells to eliminate the defective cells.Despite this system of protection, a tumor cell sometimes manages to avoid having stress-induced proteins placed on its surface, allowing it to remain undetected by the immune system. By studying several different types of human cancer cells, Schmiedel et al. found that a protein called IMP3 is present in cancer cells but not in healthy cells. Further investigation revealed that IMP3 prevents the production of some stress-induced proteins and stops them moving to the cell surface.Schmiedel et al. also show that the presence of the IMP3 protein in cancer cells causes nearby immune cells to become much less active. This suggests that developing drugs that block the activity of IMP3 could help the immune system to fight back and destroy cancer cells.