Development and validation of an interferon signature predicting prognosis and treatment response for glioblastoma

Abstract

Background: Interferon treatment, as an important approach of anti-tumor immunotherapy, has been implemented in multiple clinical trials of glioma. However, only a small number of gliomas benefit from it. Therefore, it is necessary to investigate the clinical role of interferons and to establish robust biomarkers to facilitate its application. Materials and methods: This study reviewed 1,241 glioblastoma (GBM) and 1,068 lower grade glioma (LGG) patients from six glioma cohorts. The transcription matrix and clinical information were analyzed using R software, GraphPad Prism 7 and Medcalc, etc. Immunohistochemical (IHC) staining were performed for validation in protein level. Results: Interferon signaling was significantly enhanced in GBM. An interferon signature was developed based on five interferon genes with prognostic significance, which could reflect various interferon statuses. Survival analysis showed the signature could serve as an unfavorable prognostic factor independently. We also established a nomogram model integrating the risk signature into traditional prognostic factors, which increased the validity of survival prediction. Moreover, high-risk group conferred resistance to chemotherapy and high IFNB1 expression levels. Functional analysis showed that the high-risk group was associated with overloaded immune response. Microenvironment analysis and IHC staining found that high-risk group occupied a disorganized microenvironment which was characterized by an enrichment of M0 macrophages and neutrophils, but less infiltration of activated nature killing (NK) cells and M1 type macrophages. Conclusion: This interferon signature was an independent indicator for unfavorable prognosis and showed great potential for screening out patients who will benefit from chemotherapy and interferon treatment.

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

“…Studies that evaluated infiltration of malignant gliomas by NK cells have reported different findings, ranging from the presence of insignificant NK cell numbers to large NK cell infiltrates in up to 89% of glioblastomas (26, 27). Another study described less infiltration of high-risk gliomas with NK cells and M1-like macrophages than lower grade gliomas (28). Therefore, differences in the subtype and stage of the disease, treatment history and permeability of the blood-brain barrier (BBB) appear to affect the likeliness of infiltration by NK cells.…”

Reprogramming of stromal fibroblasts by chemotherapy-induced secretion of IFNβ1 drives re-growth of breast cancer cells after treatment

“…In recent years, the secretome of cancer cells and its impact on therapy response has gained attention and numerous studies explore its role in several aspects of tumour including in which compartment of the tumour this pathway is activated. Moreover, high expression of interferon-regulated genes in several tumour entities also strongly correlated with a worse outcome in patients 37,38 . All of these studies highlight the high degree of plasticity of type I IFN and the need for a better understanding of the role of this pathway in the context of cancer.…”

Randomized Controlled Immunotherapy Clinical Trials for GBM Challenged

“…Immunomodulation with checkpoint inhibitors is considered to belong to the domain of tumor-agnostic treatments [ 47 ]. Immunotherapies generally do not point to the molecular biological characteristics inside tumor cells, but, rather, to the surface of tumor cells, including a heterogeneous number of known and unknown tumor antigens [ 67 ] and immune costimulatory and inhibitory molecules on the surface [ 68 , 69 , 70 ], as well as the production of cytokines and chemokines that influence the immune system and the inflammatory response [ 71 ]. Terms like “cold” versus “hot” tumors, describing differences in lymphocyte infiltration in the tumor microenvironment, have become highly relevant [ 72 ].…”