IMMU-58. REDUCED NEOANTIGEN EXPRESSION AS A POSSIBLE IMMUNE EVASION MECHANISM DURING GLIOMA PROGRESSION

Limited success of immune-based therapies in glioma might be in part due to the lack of enough neoantigens (neoAgs) that can be targeted by immune effector cells. In addition, gliomas also show dynamic clonal evolution over time, possibly leading to immunoediting during progression. In this study, we evaluated neoAg expression change and its relation to immune microenvironment using matched primary and recurrent tumor samples from 25 glioma patients [8 IDH-wildtype glioblastoma (GBM), 9 IDH-mutant astrocytoma (LGG-A), and 8 oligodendroglioma (LGG-O)]. Predicted neoAgs (p-neoAgs) deriving from missense mutations were identified by whole-exome sequencing (WES) analysis and the MHC class I binding prediction algorism NetMHCpan2.8. Expressed neoAgs (e-neoAgs) among the p-neoAgs were determined by incorporating RNA sequencing (RNA-seq) data. The ratio of e-neoAgs to p-neoAgs (“neoAg expression ratio”) on each sample significantly decreased at recurrence (p = 0.003) and was particularly strong in neoAg with a higher affinity for MHC class I. Similar results were obtained for GBM, LGG-A, and LGG-O, when separately analyzed. RNA-seq-based differential gene expression analyses including gene ontology analysis and pair-designed gene set enrichment analysis illustrated that the cases with strongly reduced neoAg expression ratio compared to primary counterpart (top 8), but not those without (bottom 8), retained gene expression related to antigen presentation machinery and gained immune effector cells at recurrence. These in silicofindings were consistent with immunohistochemistry for CD8 and MHC class I on tumor samples. These data may suggest that the tumor cells with reduced neoAg expression survived at recurrence as a result of persistent anti-tumor immune responses in some gliomas under the standard treatment. Reduced neoAg expression and impaired APM during progression may play complementary roles in the immune evasion of gliomas.