IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA: a systematic review.

Abstract

In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.