Abstract
Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient’s clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas’ potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis.
Highlights
A glioma, accounting for 81% of malignant brain tumors, is a primary brain tumor originating from glial stem cells or progenitor cells [1, 2]
Multiple studies reported that the CXCL family played a critical role in tumorigenesis, tumor cell proliferation and metastasis, tumor cell resistance to drugs, and tumor angiogenesis [17,18,19,20]
The STAT3 inhibitor can target the central nervous system tumor by induing immunocyte tumor homing in a CXCL10-dependent manner [22]
Summary
A glioma, accounting for 81% of malignant brain tumors, is a primary brain tumor originating from glial stem cells or progenitor cells [1, 2]. The malignancy of gliomas is attributed to its rapid cell proliferation and abnormal angiogenesis [3]. World Health Organization graded gliomas from I to IV based on tumor histological features. Grade IV gliomas, known as GBM, progress aggressively, show high recurrence rate, and are resistant to tumor treatment, along with median survival time less than 14.6 months. Molecular biomarkers like IDH status, MGMT promoter status, 1p19q, ARTX have been considered as glioma progression-associated marker. Classical, and proneural was proposed to assist in predicting glioma progression. Current standard treatment for gliomas includes maximal surgical removal combined with radio-chemotherapy, but patients’ survival outcome is still unsatisfactory [4]. The exploration of potential biomarkers may benefit glioma patients and assist in clinical treatment decision
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