Features and therapeutic potential of T-cell receptors in high-grade glioma

摘要

Background:Previous studies have shown that endogenous T cells play an important role in the prolonged survival time of high-grade glioma (HGG) patients.Our objectives were to investigate the features of T-cell receptor (TCR) repertoires in HGG patients and to elucidate any potential therapeutic value.Methods:During November 2011 and December 2018,tumor tissues and blood samples of 35 patients with HGG who underwent surgery at Beijing Tiantan Hospital or Beijing Shijitan Hospital were selected after surgery.After isolating DNA from samples,multiple rounds of PCR were performed to establish a DNA immune repertoire (IR).Then,the sequences and frequencies of the complementarity-determining 3 (CDR3) region in TCR beta chain (TRB) were identified by high-throughput sequencing and IR analysis.A survival follow-up was conducted monthly thereafter until December 2018.Finally,the t test and Mann-Whitney test were used to compare statistical differences between two sets of data.Results:The Shannon diversity index (SHDI) of TRB sequences of HGG patients was significantly lower than that of healthy individuals (7.34 vs.8.45,P =0.001).The SHDI of TRB sequences of glioblastoma (GBM) patients with more than 16 months survival time was much higher than that of GBM patients with shorter survival times in both tumor tissues (3.48 ± 0.31 vs.6.21 ± 0.33,t =-5.49,P =0.002) and blood cells (6.02 ± 0.66 vs.7.44 ± 0.32,t =-2.20,P =0.036).In addition,patients achieved a distinctly higher proportion compared to that of healthy individuals in the proportion of TRBV9 and TRBV5 functional regions (9.83 ％ vs.6.83％,P =0.001).Surgical tissue from patients who survived more than 16 months yielded a much higher proportion of TRBV4 and TRBV9 regions (7.14％ vs.3.28％,t =3.18,P =0.019).In surgical tissues from two GBM patients who survived for longer than 46 months,we found a potentially therapeutic TCR sequence.Conclusions:HGG patients have less species diversity of TCR repertoires compared with that of healthy individuals.TRBV9 regions in TCRs may be protective factors for long-term survival of GBM patients.