Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin.
Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neuropathologie Laboratoire Escourolle, Paris, France.
Curr Opin Oncol. 2021 Nov 1;33(6):626-634. doi: 10.1097/CCO.0000000000000787.
Recent evidence suggests high tumor mutational burden (TMB-H) as a predictor of response to immune checkpoint blockade (ICB) in cancer. However, results in TMB-H gliomas have been inconsistent. In this article, we discuss the main pathways leading to TMB-H in glioma and how these might affect immunotherapy response.
Recent characterization of TMB-H gliomas showed that 'post-treatment' related to mismatch repair (MMR) deficiency is the most common mechanism leading to TMB-H in gliomas. Unexpectedly, preliminary evidence suggested that benefit with ICB is rare in this population. Contrary to expectations, ICB response was reported in a subset of TMB-H gliomas associated with constitutional MMR or polymerase epsilon (POLE) defects (e.g., constitutional biallelic MMRd deficiency). In other cancers, several trials suggest increased ICB efficacy is critically associated with increased lymphocyte infiltration at baseline which is missing in most gliomas. Further characterization of the immune microenvironment of gliomas is needed to identify biomarkers to select the patients who will benefit from ICB.
Intrinsic molecular and immunological differences between gliomas and other cancers might explain the lack of efficacy of ICB in a subset of TMB-H gliomas. Novel combinations and biomarkers are awaited to improve immunotherapy response in these cancers.
最近的证据表明，高肿瘤突变负荷（TMB-H）可预测癌症对免疫检查点阻断（ICB）的反应。然而，TMB-H 脑胶质瘤的结果并不一致。本文讨论了导致脑胶质瘤 TMB-H 的主要途径，以及这些途径如何影响免疫治疗反应。
TMB-H 脑胶质瘤的特征表明，与错配修复（MMR）缺陷相关的“治疗后”是导致脑胶质瘤 TMB-H 的最常见机制。出乎意料的是，初步证据表明，该人群中 ICB 的获益很少。与预期相反，在与错配修复或聚合酶 epsilon（POLE）缺陷相关的 TMB-H 脑胶质瘤亚组中（例如，错配修复缺陷），报告了 ICB 反应。在其他癌症中，几项试验表明，ICB 疗效的增加与基线时淋巴细胞浸润的增加密切相关，而大多数脑胶质瘤中均缺乏这种浸润。需要进一步对脑胶质瘤的免疫微环境进行特征分析，以确定生物标志物来选择从 ICB 中获益的患者。
脑胶质瘤与其他癌症之间内在的分子和免疫学差异可能解释了 ICB 在一部分 TMB-H 脑胶质瘤中疗效不佳的原因。需要新的联合治疗和生物标志物来提高这些癌症的免疫治疗反应。
