title: Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival.
abstract: Exosomes in plasma of glioma patients hold promise as biomarkers of prognosis. We aimed to determine whether changes in total exosomal protein and mRNA expression levels could serve as surrogate markers of immunological and clinical responses in glioma patients receiving antitumor vaccines. Exosomes were isolated from pre/post-vaccine plasma specimens in 20/22 patients enrolled in a phase I/II trial with the antitumor vaccine. Exosomal protein content was analyzed and mRNA expression levels for 24 genes were simultaneously assessed by qRT-PCR. Pre- to post-vaccination changes in exosomal protein and ΔCt values were correlated with immunological and clinical responses and survival using Spearman rank statistics and hazard ratios (HR). Exosomal protein levels positively correlated (p< 0.0043) with the WHO tumor grade at diagnosis. Protein levels were lower in post- vs. pre-vaccination exosome fractions. Post-therapy increases in tumor size were associated with elevations in exosome proteins in glioblastoma but not always in anaplastic astrocytoma (AA). Only exosomal ΔCt values for IL-8, TIMP-1, TGF-β and ZAP70 were significant (p< 0.04 top< 0.001). The ΔCt for IL-8 and TGF-β mRNA positively correlated with post-vaccine immunologic responses to glioma antigens, while ΔCt for TIMP-1 mRNA was negatively correlated to ΔCt for IL-8 and TGF-β. Only ΔCt for IL-8 weakly correlated with OS and time to progression (TTP). In post-vaccine exosomes of the longest surviving patient with AA, mRNA for PD-1 was persistently elevated. Protein and mRNA expression levels for immune-related genes in plasma exosomes were useful in evaluating glioma patients' response to vaccination therapy.
authors.affiliation: University of Pittsburgh Cancer Institute ; Pittsburgh, PA, USA ; Department of Otolaryngology and Head & Neck Surgery; University Hospital Basel ; Basel, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.affiliation: University of Pittsburgh Cancer Institute ; Pittsburgh, PA, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Muller-Haegele
authors.affiliation: Hitachi Chemical Research Center, Inc. ; Irvine, CA, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Mitsuhashi
authors.affiliation: University of Pittsburgh Cancer Institute ; Pittsburgh, PA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.affiliation: University of Pittsburgh Cancer Institute ; Pittsburgh, PA, USA ; Departments of Neurological Surgery; Surgery and Immunology; University of Pittsburgh School of Medicine ; Pittsburgh, PA, USA.
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
authors.affiliation: University of Pittsburgh Cancer Institute ; Pittsburgh, PA, USA ; Departments of Pathology; Immunology and Otolaryngology; University of Pittsburgh School of Medicine ; Pittsburgh, PA, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
keywords: AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; ATP, adenosine triphosphates; EV, extracellular vesicles; GAA, glioma associated antigens; GBM, glioblastoma multiforme; MRI, magnetic resonance imaging; NC, normal controls; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand 1; TEM, transmission electron microscopy; TEX, tumor-derived exosomes; TTP, time to progression; glioma; mRNA; plasma-derived exosomes; survival; vaccination