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.
Highlights
Glioma is the most common form of a primary malignant brain tumor in adults
Immune infiltration analysis based on a single-sample gene set enrichment analysis score can be employed to explore the degree of immune infiltration of gliomas
The findings suggest the association of low tumor purity, high immune score, high stromal score, high ESTIMATE score, and high stemness score with a high proportion of cancer-associated fibroblasts (CAFs) and the overall survival (OS) of glioma patients
Summary
Glioma is the most common form of a primary malignant brain tumor in adults. Current evidence indicates surgical resection as the main treatment approach for gliomas, postoperative radiotherapy, and chemotherapy can be administered according to the specific condition of patients. Most gliomas are difficult to completely be removed by surgery without affecting normal brain functions due to the growth properties and its special local anatomy characteristics. Some patients do not respond well to radiotherapy and chemotherapy, and develop rapid recurrence after standard therapy (Tan et al, 2020). Despite recent progress in the development of new drugs, researchers are facing challenges in developing therapeutics for gliomas due to biological properties, including the blood-brain barrier, tumor specificity of gliomas, and immune environments (Aldape et al, 2019)
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