Prognosis and Immunotherapy Significances of a Cancer-Associated Fibroblasts-Related Gene Signature in Gliomas

Zhimin Chen; Shenghua Zhuo; Guiying He; Jingzhi Tang; Weijie Hao; Wei-Qiang Gao; Kun Yang; Huiming Xu

doi:10.3389/fcell.2021.721897

Prognosis and Immunotherapy Significances of a Cancer-Associated Fibroblasts-Related Gene Signature in Gliomas

Front Cell Dev Biol. 2021 Oct 29:9:721897. doi: 10.3389/fcell.2021.721897. eCollection 2021.

Authors

Zhimin Chen¹, Shenghua Zhuo², Guiying He³, Jingzhi Tang¹, Weijie Hao¹, Wei-Qiang Gao¹, Kun Yang², Huiming Xu¹

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Neurosurgery, The First Affiliated Hospital of Hainan Medical University, Haikou, China.
³ Department of Neurology, Shenzhen Nanshan People's Hospital, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China.

Abstract

As a cold tumor, malignant glioma has strong immunosuppression and immune escape characteristics. The tumor microenvironment (TME) provides the "soil" for the survival of malignant tumors, and cancer-associated fibroblasts (CAFs) are the architects of matrix remodeling in TME. Therefore, CAFs have potent regulatory effects on the recruitment and functional differentiation of immune cells, whereby they synthesize and secrete numerous collagens, cytokines, chemokines, and other soluble factors whose interaction with tumor cells creates an immunosuppressive TME. This consequently facilitates the immune escape of tumor cells. Targeting CAFs would improve the TME and enhance the efficacy of immunotherapy. Thus, regulation of CAFs and CAFs-related genes holds promise as effective immunotherapies for gliomas. Here, by analyzing the Chinese Glioma Genome Atlas and the Cancer Genome Atlas database, the proportion of CAFs in the tumor was revealed to be associated with clinical and immune characteristics of gliomas. Moreover, a risk model based on the expression of CAFs-related six-gene for the assessment of glioma patients was constructed using the least absolute shrinkage and selection operator and the results showed that a high-risk group had a higher expression of the CAFs-related six-genes and lower overall survival rates compared with those in the low-risk group. Additionally, patients in the high-risk group exhibited older age, high tumor grade, isocitrate dehydrogenase wildtype, 1p/19q non-codeletion, O-6-methylguanine-DNA methyltransferase promoter unmethylation and poor prognosis. The high-risk subtype had a high proportion CAFs in the TME of glioma, and a high expression of immune checkpoint genes. Analysis of the Submap algorithm indicated that the high-risk patients could show potent response to anti-PD-1 therapy. The established risk prediction model based on the expression of six CAFs-related genes has application prospects as an independent prognostic indicator and a predictor of the response of patients to immunotherapy.

Keywords: cancer-associated fibroblasts; glioma; immunotherapy; prognosis; risk score; tumor microenvironment.