Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Institute of Neuroscience, Nanchang University, Nanchang, China.
Front Immunol. 2021 Sep 9;12:722479. doi: 10.3389/fimmu.2021.722479. eCollection 2021.
Epigenetic regulations of the tumor microenvironment (TME) and immunotherapy have been investigated in recent years. Nevertheless, the potential value of mitochondrial ribosomal RNA (mt-rRNA) modification in regulation of the TME and immunotherapy remains unknown.
We comprehensively investigated the mt-rRNA-modification patterns in glioma patients based on nine regulators of mt-rRNA. Subsequently, these modification patterns were correlated systematically with immunologic characteristics and immunotherapy. An "mt-rRNA predictor" was constructed and validated in multiple publicly available cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients.
Two distinct patterns of mt-rRNA modification were determined based on the evidence that nine regulators of mt-rRNA correlated significantly with most clinicopathologic characteristics, immunomodulators, TME, immune-checkpoint blockers (ICBs), and prognosis. Patients with mt-rRNA subtype II presented significantly poorer overall survival/progression-free survival (OS/PFS), but higher tumor mutational burden (TMB), more somatic mutations, and copy number variation (CNV). These two mt-rRNA subtypes had distinct TME patterns and responses to ICB therapy. An mt-rRNA predictor was constructed and validated in four glioma cohorts. The subtype with high mt-rRNA score, characterized by increased TMB, infiltration of immune cells, and activation of immunity, suggested an immune-activated phenotype, and was also linked to greater sensitivity to immunotherapy using anti-programmed cell death protein 1 (PD-1) but resistance to temozolomide.
Regulators of mt-rRNA modification have indispensable roles in the complexity and diversity of the TME and prognosis. This novel classification based on patterns of mt-rRNA modification could provide an effective prognostic predictor and guide more appropriate immunotherapy/chemotherapy strategies for glioma patients.
近年来，人们对肿瘤微环境（TME）的表观遗传调控和免疫治疗进行了研究。然而，线粒体核糖体 RNA（mt-rRNA）修饰在调节 TME 和免疫治疗中的潜在价值尚不清楚。
我们基于 9 种 mt-rRNA 调节剂全面研究了胶质瘤患者的 mt-rRNA 修饰模式。随后，系统地将这些修饰模式与免疫特征和免疫治疗相关联。构建并在多个公开可用的队列中验证了“mt-rRNA 预测器”，为胶质瘤患者的预后预测和免疫治疗提供指导。
基于 9 种 mt-rRNA 调节剂与大多数临床病理特征、免疫调节剂、TME、免疫检查点抑制剂（ICB）和预后显著相关的证据，确定了两种不同的 mt-rRNA 修饰模式。mt-rRNA 亚型 II 患者的总生存/无进展生存（OS/PFS）明显较差，但肿瘤突变负担（TMB）更高，体细胞突变和拷贝数变异（CNV）更多。这两种 mt-rRNA 亚型具有不同的 TME 模式和对 ICB 治疗的反应。构建并在四个胶质瘤队列中验证了 mt-rRNA 预测器。mt-rRNA 评分较高的亚型，其特征是 TMB 增加、免疫细胞浸润和免疫激活，提示具有免疫激活表型，并且与使用抗程序性细胞死亡蛋白 1（PD-1）的免疫治疗更敏感相关，但对替莫唑胺耐药。
mt-rRNA 修饰调节剂在 TME 和预后的复杂性和多样性中具有不可或缺的作用。这种基于 mt-rRNA 修饰模式的新分类可为胶质瘤患者提供有效的预后预测指标，并指导更合适的免疫治疗/化疗策略。
