CMTM Family Genes Affect Prognosis and Modulate Immunocytes Infiltration in Grade II/III Glioma Patients by Influencing the Tumor Immune Landscape and Activating Associated Immunosuppressing Pathways.

Zeyu Wang,Kui Yang,Xisong Liang,Hao Zhang,Jingwei Zhang,Shuwang Li,Fangkun Liu,Renjun Peng,Ziyu Dai,Zhixiong Liu,Quan Cheng,Xun Zhang

doi:10.3389/fcell.2022.740822

Abstract

Lower-grade glioma (LGG) is one of the most common primary tumor types in adults. The chemokine-like factor (CKLF)-like Marvel transmembrane domain-containing (CMTM) family is widely expressed in the immune system and can modulate tumor progression. However, the role of the CMTM family in LGG remains unknown. A total of 508 LGG patients from The Cancer Genome Atlas (TCGA) database were used as a training cohort, and 155 LGG patients from the Chinese Glioma Genome Atlas (CGGA) array database, 142 LGG patients from the CGGA RNA-sequencing database, and 168 LGG patients from the GSE108474 database were used as the validation cohorts. Patients were subdivided into two groups using consensus clustering. The ENET algorithm was applied to build a scoring model based on the cluster model. Finally, ESTIMATE, CIBERSORT, and xCell algorithms were performed to define the tumor immune landscape. The expression levels of the CMTM family genes were associated with glioma grades and isocitrate dehydrogenase (IDH) status. Patients in cluster 2 and the high-risk score group exhibited a poor prognosis and were enriched with higher grade, wild-type IDH (IDH-WT), 1p19q non-codeletion, MGMT promoter unmethylation, and IDH-WT subtype. Patients in cluster 1 and low-risk score group were associated with high tumor purity and reduced immune cell infiltration. Enrichment pathways analysis indicated that several essential pathways involved in tumor progression were associated with the expression of CMTM family genes. Importantly, PD-1, PD-L1, and PD-L2 expression levels were increased in cluster 2 and high-risk groups. Therefore, the CMTM family contributes to LGG progression through modulating tumor immune landscape.

Highlights

Gliomas originate from the neuroglial stem or progenitor cells and is the most common primary malignant brain tumor (Weller et al, 2015)
The result indicated that the levels of CMTM3, CMTM6, CMTM7, CMTM8, and chemokine-like factor (CKLF) were much higher in isocitrate dehydrogenase (IDH)-WT than in IDH-mutated gliomas in the The Cancer Genome Atlas (TCGA) database (p < 0.001; Figure 2D)
Data from the CGGA301 database showed that only CMTM8 was upregulated in IDH-WT compared with the IDH mutational group (p < 0.01; Figure 2E), which could be due to fewer samples in CGGA301 than TCGA database

Summary

Introduction

Gliomas originate from the neuroglial stem or progenitor cells and is the most common primary malignant brain tumor (Weller et al, 2015). Gliomas are classified into two categories according to the degree of malignancy, including glioblastoma (GBM) and lower-grade glioma (LGG). 2016 WHO classification of the central nervous system (CNS) tumors classified gliomas into astrocytic tumors, oligodendrogliomas, and not otherwise specified (NOS) based on histology and molecular features, including isocitrate dehydrogenase (IDH) mutational and 1p/19q codeletion status (Wen and Huse, 2016; Wen and Huse, 2017). People with LGG have a better prognosis than other aggressive tumor types in the CNS, the median overall survival (OS) of LGG is still far from satisfactory (Sidaway, 2020; Aiman and Rayi, 2021)

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Conclusion