Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas

SIMPLE SUMMARY: Tumor mutation burden (TMB) has shown promise as a biomarker for immune checkpoint blockade therapy in some cancers, but not consistently in gliomas. The goal of our study was to systematically investigate the association between TMB, expressed neoantigens, and the tumor immune microenvironment in IDH-mutant and IDH-wildtype gliomas, which are two types of biologically distinct gliomas. We demonstrated that TMB positively correlated with expressed neoantigens, but inversely correlated with immune score in IDH-wildtype tumors but showed no correlation in IDH-mutant tumors. The antigen processing and presenting (APP) score may have potential as a clinical biomarker to predict immune therapy response in gliomas. Lastly, 19% of patients had pathogenic or likely pathogenic germline mutations, primarily in DNA damage repair genes. ABSTRACT: Background: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Methods: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Results: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = −0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. Conclusion: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.