Deciphering the role of QPCTL in glioma progression and cancer immunotherapy

Abstract

BackgroundGlioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy.MethodsQPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors.ResultsIn contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness.ConclusionHigh QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

Isoglutaminyl Cyclase Overexpression Enhances KYSE30 Cancer Cell Proliferation and Migration via the MAPK Signaling Pathway

“…Various studies have shown that upregulated isoQC contributes to the initiation of disorders such as inflammation and cancer by catalyzing the generation of pE modified substrates. − However, the pathological mechanisms by which upregulated isoQC acts is unclear. Here, we aimed to understand how upregulated isoQC involves the initiation of diseases.…”

“…The cyclic conversion of N-terminal glutamate or glutamine to pyroglutamate (pE) on peptides, hormones, cytokines, and proteins is usually required for their maturation and physiological activity. , However, the abnormal generation of pE-modified substrates contributes to the initiation of diseases including Alzheimer’s disease and cancer. − …”

Glioblastoma Phagocytic Cell Death: Balancing the Opportunities for Therapeutic Manipulation

“…Glutaminyl-peptide cyclotransferase-like protein (QPCTL) regulates the CD47-SIRPα interaction by facilitating the formation of pyroglutamate (pGlu) on CD47 at the SIRPα binding site [42]. Preclinical studies have identified candidate smallmolecule inhibitors of QPCTL, such as luteolin and ISM004-1057D, that suppress the pGlu modification of CD47 and reduce its binding affinity to SIRPα [43,44]. Furthermore, the transcription factor Myc has been identified as a direct regulator of CD47 expression [45].…”

A comparative <i>in vitro</i> study on the effect of SGLT2 inhibitors on chemosensitivity to doxorubicin in MCF-7 breast cancer cells

“…It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in the mtDNA repair system and mitochondrial nucleoid protection. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients [ 3 ]. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear [ 4 ].…”