PATH-31. GIANT CELL GLIOBLASTOMAS: ANALYSIS OF MISMATCH-REPAIR (MMR) PROTEINS EXPRESSION, POLIMERASE ε (POLE) MUTATIONS AND THEIR ROLE IN TUMOR IMMUNORESPONSE

Abstract

Giant cell glioblastoma (gcGBM) is a rare (<1%) variant glioblastoma (GBM), in younger patients. Unlike the IDH-wild type GBM, they have a better prognosis. Mutations in the POLE and in MMR genes accelerate tumorigenesis, generating in some tumours an ultra-mutated phenotype. The lack of proofreading activity generates production of neoantigens, recalling tumour infiltrating lymphocytes, and immune-checkpoint ligands exposition. Aim of our study was to investigate MMR proteins expression, POLE mutations, related checkpoint molecules and the tumor immunemicroenvironment in a group of gcGBMs compared to IDH-wild type GBMs. We performed a molecular and immunohistochemical analysis on 60 primary gcGBMs. All tumours where characterized for EGFR, PTEN, p53, IDH1, MGMT status by immunohistochemistry and/or molecular analysis. We investigated MMR protein (MSH6, MSH2, PML2 and MLH1), PD-L1, CTLA-4 and CD28 expression by immunohistochemistry in gcGBMs and in a group of standard GBMs. POLE mutations have been studied by direct sequencing of exons encoding its exonuclease activity. Then we assess the immunological status investigating the presence of lymphocytic infiltrates, microglia and macrophages, by CD3, CD4, CD8, CD68, CD163, MHC class II and IBA1. All the results obtained have been related to clinical data. The median survival time was 21 months, with 4 patients long survivors (>5 years), higher than in the standard group. The main findings where partial loss of expression of MMR proteins (overall MSH2 and MSH6) on 30% of cases, mostly related to presence of inflammatory infiltrates, also showing CD28 immunostaining. Microglia IBA1+ was significantly present in patients with longer survival. Correlation with PD-L1 and CTLA4 was found only in 2 cases. POLE sequencing displays mutation F367S on 20% of cases. Our results show that gcGBMs are an histological variant with increased tendency to ultra-mutated phenotype with a better prognosis and suggesting these patients as candidates for immunotherapy.