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.
Highlights
Cancer immunotherapy is one of the recent breakthroughs in cancer treatment
We started our analysis of potentially survival-related factors with for the treatment group this unsupervised an exploratory proteomics phase to establish feasibility of protein approach did not produce significant results, the control group samples segrehad at our disposal
Candidates possibly related to ST survival that we identified in the immunotherapy group were Huntingtin interacting protein 1 (HIP1), retinol binding protein 1 (RBP1), C9orf[64], FTH1, MAP1LC3A and FAK2—even if the latter three were only detectable in multivariate analyses
Summary
Cancer immunotherapy is one of the recent breakthroughs in cancer treatment. For many malignant diseases, it has brought a remarkable improvement in outcomes.[1]. Immune checkpoint inhibitors block inhibitory immunoregulatory signaling loops such as CTLA-4 or PDL-1/PD-1 and led to remarkable survival improvements in cancers like melanoma.[9] In glioblastoma, interim results from a phase III clinical trial were disappointing.[10] Oncolytic viruses are designed to directly destroy glioblastoma cells and to activate immunogenic cell death pathways leading to a stimulation of immuneresponses. They are still in early clinical development phases.[8] CAR
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