P06.15 IFI16 expression in gliomas and its potential role in immunosurveillance

In glial tumors the immune-escape is an important mechanism to promote invasion and aggressiveness, thus the aim of our study was to investigate the expression of Interferon inducible protein 16 (IFI16) in human gliomas. IFI16 is a member of the p200 human family proteins that share highly conserved repeats at C-terminus which allow them to bind dsDNA and a typical protein-protein interaction domain at their N-terminus. IFI16 gene is located at 1q23.1 chromosome and encodes for three isoforms of IFI16: its functions ranging from transcriptional regulation, apoptosis, cell growth regulation and differentiation. But, the most intriguing function of IFI16 is its role in the immunomodulation of innate and adaptive immunity. IFI16 protein is located in the nucleolar compartment where it is able to activate and fine-tune the transcription, while when it is located in the nucleoplasm is probably inactive. We have studied IFI16 expression in 120 gliomas (40 grade II, 40 grade III and 40 glioblastomas) by immunohistochemistry, using two antibodies against the C- and N-terminus, and molecular biology techniques. All these cases were also evaluated for p53, IDH1(R132H), MGMT methylation status and LOH of chromosomes 1p, 19q, 9p, 17p and 10q. We found a strong nucleolar expression of IFI16 in astrocytic lower grade gliomas and this expression was strictly related to p53 nuclear expression: this co-localization was demonstrated by confocal analysis and suggests a role of IFI16 as tumor suppressor. In grade III gliomas and glioblastomas, instead, IFI16 was mostly expressed in the nucleoplasm: this shift to the inactive form is related to a shorter survival suggesting a role as prognostic factor. In oligodendrogliomas IFI-16 expression was completely absent and it is strictly related to 1p/19q co-deletion, but with intact IFI16 gene, as showed by array-CGH analysis. As a final point, we have characterized tumor inflammatory infiltrates using antibodies against CD3, CD4, CD8, CD68 and FoxP3 related to IFI16 expression and tumor survival. Particularly in glioblastomas we observed a major expression of CD3+/CD4+ lymphocytes in the cases with strong nucleoplasm IFI16 expression and shorter survival; while CD3+/CD8+ cells were present in glioblastomas with nucleolar expression and longer survival, with also a strong activation of both microglia and macrophages, suggesting an active role of IFI16 in immuno-surveillance. In conclusion, this is the first study of IFI16 in gliomas, and we identify IFI16 as a new potential prognostic factor, highlighting its early role in proliferation, malignant progression and immunomodulation of these tumours.