Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

Abstract

Background Glioblastoma (GBM) is considered the most malignant and devastating intracranial tumor without effective treatment. Autophagy, apoptosis, and necrosis, three classically known cell death pathways, can provide novel clinical and immunological insights, which may assist in designing personalized therapeutics. In this study, we developed and validated an effective signature based on autophagy-, apoptosis- and necrosis-related genes for prognostic implications in GBM patients. Methods Variations in the expression of genes involved in autophagy, apoptosis and necrosis were explored in 518 GBM patients from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were performed to construct a combined prognostic signature. Kaplan–Meier survival, receiver-operating characteristic (ROC) curves and Cox regression analyses based on overall survival (OS) and progression-free survival (PFS) were conducted to estimate the independent prognostic performance of the gene signature. The Chinese Glioma Genome Atlas (CGGA) dataset was used for external validation. Finally, we investigated the differences in the immune microenvironment between different prognostic groups and predicted potential compounds targeting each group. Results A 16-gene cell death index (CDI) was established. Patients were clustered into either the high risk or the low risk groups according to the CDI score, and those in the low risk group presented significantly longer OS and PFS than the high CDI group. ROC curves demonstrated outstanding performance of the gene signature in both the training and validation groups. Furthermore, immune cell analysis identified higher infiltration of neutrophils, macrophages, Treg, T helper cells, and aDCs, and lower infiltration of B cells in the high CDI group. Interestingly, this group also showed lower expression levels of immune checkpoint molecules PDCD1 and CD200, and higher expression levels of PDCD1LG2, CD86, CD48 and IDO1. Conclusion Our study proposes that the CDI signature can be utilized as a prognostic predictor and may guide patients’ selection for preferential use of immunotherapy in GBM.

Comprehensive Analyses of Ferroptosis-Related Alterations and Their Prognostic Significance in Glioblastoma

“…In this study, the results of these two analyses showed significant differences in different risk score subgroups (Supplementary Figure S6A-E), further supporting the feasibility of the risk score model to be used for the clinical prognostic assessment. Subsequent immune checkpoint analyses revealed that the expressions of CD274, CTLA4, PDCD1, and LAG3 in the high-risk group were significantly higher than those of the low-risk group, suggesting that the high expression of related genes might be one of the reasons that affected GBM treatment and prognosis (Supplementary Figure 6F-I), which was also consistent with previous reports on the correlation between those four genes and the glioblastoma prognosis (Andrews et al, 2020;Du et al, 2020;Yang et al, 2021;Bi et al, 2022;Preddy et al, 2022).…”

Development and experimental validation of an M2 macrophage and platelet‐associated gene signature to predict prognosis and immunotherapy sensitivity in bladder cancer

“…Recently, the establishment of diagnosis or prognosis models from the particular aspect of biological processes, such as ferroptosis, 45,46 necrosis, 47 lipid metabolism, 48,49 and acetylation, 50 and the tumor immune microenvironment, 51,52 has attracted increasing interest.…”

Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression

“…Additionally, while the control sphere, U87MG, revealed Ki-67 positivity of about 40%, the neutrophil groups, in both initial and advanced tumor 3D models, reached a plateau of about 80%, demonstrating that growth was significantly higher when there is crosstalk between these cells. Necrosis is a relevant finding in clinical tumor samples, being an indication of malignancy ( 35 ). Thus, since our experiments revealed increased levels of necrosis in the presence of neutrophils, it is suggested that neutrophils could help in inducing necrosis within the tumor niche, favoring the poor prognosis in glioma patients.…”