Development and Validation of an IDH1-Associated Immune Prognostic Signature for Diffuse Lower-Grade Glioma.

Xiangyang Deng,Zelin Yang,Jian Lin,Nu Zhang,Liang Yang,Xiaojia Zhang,Xingxing Xu,Xuchao Shen,Bo Chen,Bo Yin,Hansong Sheng,Xiangqi Lu,Dongdong Lin

doi:10.3389/fonc.2019.01310

Abstract

A mutation in the isocitrate dehydrogenase 1 (IDH1) gene is the most common mutation in diffuse lower-grade gliomas (LGGs), and it is significantly related to the prognosis of LGGs. We aimed to explore the influence of the IDH1 mutation on the immune microenvironment and develop an IDH1-associated immune prognostic signature (IPS) for predicting prognosis in LGGs. IDH1 mutation status and RNA expression were investigated in two different public cohorts. To develop an IPS, LASSO Cox analysis was conducted for immune-related genes that were differentially expressed between IDH1wt and IDH1mut LGG patients. Then, we systematically analyzed the influence of the IPS on the immune microenvironment. A total of 41 immune prognostic genes were identified based on the IDH1 mutation status. A four-gene IPS was established and LGG patients were effectively stratified into low- and high-risk groups in both the training and validation sets. Stratification analysis and multivariate Cox analysis revealed that the IPS was an independent prognostic factor. We also found that high-risk LGG patients had higher levels of infiltrating B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells, and expressed higher levels of CTLA-4, PD-1 and TIM-3. Moreover, a novel nomogram model was established to estimate the overall survival in LGG patients. The current study provides novel insights into the LGG immune microenvironment and potential immunotherapies. The proposed IPS is a clinically promising biomarker that can be used to classify LGG patients into subgroups with distinct outcomes and immunophenotypes, with the potential to facilitate individualized management and improve prognosis.

Highlights

Gliomas are the most commonly occurring type of malignant primary tumor of the central nervous system, which arise from astrocytic, oligodendroglial, mixed oligoastrocytic, or neuronal-glial cells, and result in significant morbidity and mortality [1, 2]
Considering the differences in immune gene expression between IDH1wt and IDH1mut patients, we evaluated the prognostic value of differentially expressed immune genes (DEIGs) by Kaplan-Meier analysis
Mounting evidence reveals that the immunological tumor microenvironment of the gliomas differs based on their isocitrate dehydrogenase 1 (IDH1) mutation [15]

Summary

Introduction

Gliomas are the most commonly occurring type of malignant primary tumor of the central nervous system, which arise from astrocytic, oligodendroglial, mixed oligoastrocytic, or neuronal-glial cells, and result in significant morbidity and mortality [1, 2]. According to the WHO classification system based on the histological type, diffuse lower-grade gliomas (LGGs) have a grade of II or III [3]. Some studies have indicated that key components of the immune response were significantly altered in gliomas, and subsequently led to immune evasion of tumors [5, 6]. In addition to conventional treatment methods including surgery, radiotherapy and chemotherapy, immunotherapy is rapidly emerging as a promising treatment modality and works by evoking an anti-tumor immune response that inhibits immune evasion by the tumor. A number of immune-related parameters have been discovered to predict the outcomes of LGG patients [7, 8]. Few studies have systematically explored the immune microenvironment of LGG

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