Combined proteomics/miRNomics of dendritic cell immunotherapy-treated glioblastoma patients as a screening for survival-associated factors

Abstract

Glioblastoma is the most prevalent and aggressive brain cancer. With a median overall survival of ~15–20 months under standard therapy, novel treatment approaches are desperately needed. A recent phase II clinical trial with a personalized immunotherapy based on tumor lysate-charged dendritic cell (DC) vaccination, however, failed to prolong survival. Here, we investigated tumor tissue from trial patients to explore glioblastoma survival-related factors. We followed an innovative approach of combining mass spectrometry-based quantitative proteomics (n = 36) with microRNA sequencing plus RT-qPCR (n = 38). Protein quantification identified, e.g., huntingtin interacting protein 1 (HIP1), retinol-binding protein 1 (RBP1), ferritin heavy chain (FTH1) and focal adhesion kinase 2 (FAK2) as factor candidates correlated with a dismal prognosis. MicroRNA analysis identified miR-216b, miR-216a, miR-708 and let-7i as molecules potentially associated with favorable tissue characteristics as they were enriched in patients with a comparably longer survival. To illustrate the utility of integrated miRNomics and proteomics findings, focal adhesion was studied further as one example for a pathway of potential general interest.Taken together, we here mapped possible drivers of glioblastoma outcome under immunotherapy in one of the largest DC vaccination tissue analysis cohorts so far—demonstrating usefulness and feasibility of combined proteomics/miRNomics approaches. Future research should investigate agents that sensitize glioblastoma to (immuno)therapy—potentially building on insights generated here.

Laryngeal Squamous Cell Carcinoma: Potential Molecular Mechanism and Prognostic Signature Based on Immune-Related Genes

“…In papillary thyroid carcinoma, with which IL13RA2 has been associated, the gene may be involved in cell migration by enhancing the epithelial-mesenchymal transition. RBP1 may be a factor associated with poor prognosis in glioblastoma [ 31 ]. RORC is thought to trigger proliferation of bladder cancer cells, and this process likely results from its ability to inhibit the PD-L1 /integrin beta-6/signal transducer and activator of transcription 3 signal axis [ 60 ].…”

“…Similarly, in esophageal squamous cell carcinoma, patients with TUBB3 -negative carcinomas had higher rates of disease-free survival (DFS) and overall survival (OS) rates than those with TUBB3 -positive disease [ 30 ]. In glioblastomas, another IRG, RBP1 , is considered to be associated with poor prognosis [ 31 ]. Studies of LSCC and IRGs have found that programmed death-ligand 1 (PD-L1) expression is associated with favorable prognosis [ 32 ], and STC2 [ 33 ] overexpression is associated with poor prognosis.…”

Putting Proteomics Into Immunotherapy for Glioblastoma

“…Besides, the proteomics from different cells would be quite different which is even suitable for the research of heterogenetic characteristics. For now, the proteomics has been tried for the evaluation of therapeutic effects on glioblastoma ( 64 ).…”

Are In Vitro Human Blood–Brain–Tumor-Barriers Suitable Replacements for In Vivo Models of Brain Permeability for Novel Therapeutics?

“…Malignant tumors of the brain and central nervous system (CNS) are among the most rapidly lethal types of cancer [1,2]. Patients diagnosed with high grade gliomas (HGG) have a poor median survival of 14-21 months for adult glioblastoma (GBM) [3] and 4-17 months for pediatric diffuse midline glioma (previously called diffuse intrinsic pontine glioma, DIPG) [4]. Limited advancements in therapeutic options mean that survival rates for GBM and DIPG patients have remained largely unchanged over the last 30 years [5].…”