Abstract
BACKGROUND: Specific herpesviruses have been implicated in glioma development. We undertook a pilot study to examine whether herpesviruses-specific human T-cell receptor (TCR) sequences in patient blood samples associate with glioma grade and survival. METHODS: The study was based on 56 pretreatment blood samples collected from both patients with glioblastoma (n = 36) with varying survival times as well as 20 lower grade glioma patients, including astrocytomas and oligodendrogliomas. Following PCR amplification and high-throughput sequencing of DNA extracted from peripheral blood, data were analyzed (AdaptiveBiotechnologies ImmunoSEQ Analyzer) to identify complementarity-determining (CDR3) regions of human TCRs specific to herpes viral antigens. We identified sequences specific for six cytomegalovirus (CMV) peptides and ten Epstein-Barr virus peptides. No CDR3 sequences specific for Varicella Zoster could be identified in the publicly available databases queried. RESULTS: Blood samples yielded large numbers of productive rearrangements (ie CDR3 sequences resulting in functional T-cell immunity), and one or more sequences targeting CMV and EBV were found in every patient sample. For both EBV and CMV, we observed a greater breadth (higher average number of unique CDR3 sequences) and intensity (higher average sum of all CDR3 sequences) of antiviral T-cell response in patients with lower-grade gliomas compared with glioblastoma, even after adjustment for patient age and sex in multivariate regression models. CONCLUSIONS: Interrogation of blood samples for CDR3 sequences describing the human TCR repertoire offers a novel tool for investigating anti-viral immune response in glioma. More robust immunity to herpesviruses could result in cross-reactive, primed cyto-toxic immune responses that potentially suppress development of more aggressive tumors.