T-cell receptor sequencing for detection of Epstein-Barr and cytomegalovirus-specific immune responses in glioma patients: An exploratory study.

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.