Human Mitochondrial Ribosomal RNA Modification-Based Classification Contributes to Discriminate the Prognosis and Immunotherapy Response of Glioma Patients.

Peng Wang,Xingen Zhu,Miaojing Wu,Jingying Li,Kai Huang,Minghua Ye

doi:10.3389/fimmu.2021.722479

Abstract

BackgroundEpigenetic 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.MethodsWe 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.ResultsTwo 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.ConclusionsRegulators 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.

Highlights

Gliomas are the most common primary intracranial tumors of the central nervous system
Considering the possible biological functions of mt-rRNAmodification enzymes in gliomas, we conducted a comprehensive study on these regulators in The Cancer Genome Atlas (TCGA) cohort
We observed that the genomic alterations of the nine regulators of mitochondrial ribosomal RNA (mt-rRNA) modification were very rare (≤1.2% for all) (Supplementary Figure S3A) in gliomas using the “cBioPortal” of TCGA

Summary

Introduction

Gliomas are the most common primary intracranial tumors of the central nervous system. Of the subtypes of gliomas, glioblastomas are the most malignant and deadliest [1,2,3]. Developments in epigenetics and immunology have enabled molecular-targeted therapies and immunotherapies for gliomas. Most of these potential new therapies are being tested in clinical trials and have not been found to significantly lengthen the survival of patients suffering from glioma [5, 6]. Epigenetic regulations of the tumor microenvironment (TME) and immunotherapy have been investigated in recent years. The potential value of mitochondrial ribosomal RNA (mt-rRNA) modification in regulation of the TME and immunotherapy remains unknown

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