Expression of key unfolded protein response genes predicts patient survival and an immunosuppressive microenvironment in glioblastoma

Abstract

Abstract Background Dysregulation of cellular processes related to protein folding and trafficking leads to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), triggering ER stress. Cells cope with ER stress by activating the unfolded protein response (UPR), a signaling pathway that has been implicated in a variety of diseases, including cancer. However, the role of the UPR in cancer initiation and progression is still unclear. Methods Here we used bulk and single cell RNA sequencing data to investigate ER stress-related gene expression in glioblastoma, as well as the impact key UPR genes have on patient survival. Results ER stress-related genes are highly expressed in both cancer cells and tumor-associated macrophages, with evidence of high intra- and inter-tumor heterogeneity. Elevated levels of the UPR-related genes, namely HSPA5, P4HB, and PDIA4, have been identified as risk factors, while high MAPK8 (JNK1) expression emerges as a protective factor in glioblastoma patients, underscoring the prognostic relevance of UPR genes in this cancer type. Finally, the expression patterns of XBP1 and MAPK8, crucial downstream targets of the ER sentinel IRE1α, show significant correlation with the presence of immune cell subtypes associated with immunosuppression and a worse patient outcome. These findings suggest a link between the expression of these genes, the immunosuppressive tumor microenvironment, and the overall survival of individuals with glioblastoma. Conclusions We performed a comprehensive transcriptional characterization of the unfolded protein response in glioblastoma patients and identified UPR-related genes associated with glioblastoma patient survival. These findings hold promise for the development of valuable prognostic and predictive biomarkers, offering insights into potential targets for the advancement of therapeutic approaches in glioblastoma treatment.