Abstract
Simple SummaryTumor 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.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.
Highlights
Gliomas are the most common primary malignant brain tumor and remain a fatal disease [1]
We focused on a systematic assessment of the tumor mutation burden (TMB), expressed neoantigens, and the tumor immune microenvironment in both Isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant gliomas, which have distinct tumor biology
While TMB had a positive correlation with expressed neoantigens, it showed an inverse correlation with immune scores in IDH-wildtype gliomas and no correlation in IDH-mutant gliomas
Summary
Gliomas are the most common primary malignant brain tumor and remain a fatal disease [1]. Tumor mutation burden (TMB), which is often proportional to the neoantigen burden, has emerged as a promising predictive biomarker of immune response in melanoma and lung cancer [4] These efforts are highlighted in the KEYNOTE-158 study, which led to the recent US Food and Drug Administration (FDA) approval of using pembrolizumab, an anti-PD1 immune checkpoint inhibitor, in solid tumors with a TMB above 10 mutations per mega base (Mb) (defined as having a hypermutator phenotype (HMP) [5]. This correlation between TMB and response to immunotherapy has not been consistently observed in gliomas [6,7]. Studies of germline variants in a larger glioma cohort are warranted
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