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.

中文翻译：

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IDH 突变、神经胶质瘤免疫原性和原发性错配修复缺陷 IDH 突变型星形细胞瘤 PMMRDIA 的治疗挑战：系统评价

2021 年，Suwala等人。将原发性错配修复缺陷型 IDH 突变型星形细胞瘤 (PMMRDIA) 描述为一组独特的神经胶质瘤。在无监督聚类中，PMMRDIA 形成独特的聚类，与其他 IDH 突变神经胶质瘤分开，包括具有继发性错配修复 (MMR) 缺陷的 IDH 突变神经胶质瘤。在已发表的队列中，三名患者接受了免疫检查点阻断剂 (ICB) 治疗，但没有人表现出反应，这与 IDH 突变型胶质瘤与 IDH 野生型相比免疫原性降低的现有知识相符。就 PMRDIA 而言，由于 MMR 缺陷而导致对替莫唑胺标准护理的固有耐药性是另一个挑战。众所周知，IDH1/2 基因的功能获得性突变会产生致癌代谢物 R-2-羟基戊二酸 (R-2-HG)，它会增加 DNA 和组蛋白甲基化，从而导致特征性神经胶质瘤相关的 CpG 岛甲基化表型。 G-CIMP）。虽然其他因素可能参与重塑 IDH 突变神经胶质瘤的肿瘤微环境 (TME)，但本系统综述强调了 R-2-HG 和随后的 G-CIMP 在免疫抑制中的作用。这凸显了增强 ICB 反应的潜在可行途径，这可能与解决 PMRDIA 未满足的治疗挑战相关。