Blood-based T cell receptor anti-viral CDR3s are associated with worse overall survival for neuroblastoma

Abstract

With the advent of large collections of adaptive immune receptor recombination reads representing cancer, there is the opportunity to further investigate the adaptive immune response to viruses in the cancer setting. This is a particularly important goal due to longstanding but still not well-resolved questions about viral etiologies in cancer and viral infections as comorbidities. In this report, we assessed the T cell receptor complementarity determining region-3 (CDR3) amino acid (AA) sequences, for blood-sourced TCRs from neuroblastoma (NBL) cases, for exact AA sequence matches to previously identified anti-viral TCR CDR3 AA sequences. Results indicated the presence of anti-viral TCR CDR3 AA sequences in the NBL blood samples highly significantly correlated with worse overall survival. Furthermore, the TCR CDR3 AA sequences demonstrating chemical complementarity to many cytomegalovirus antigens represented cases with a worse outcome, including cases where such CDR3s were obtained from tumor samples. Overall, these results indicate a significant need for, and provide a novel strategy for assessing viral infection complications in NBL patients.

Keywords: Anti-viral complementarity determining region-3; CMV; Co-morbidities; Neuroblastoma; T cell receptor.

Fig. 1

Kaplan–Meier (KM) overall survival (OS) analysis representing case IDs with or without anti-CMV CDR3s and with or without MYCN amplification. A Case IDs without MYCN amplification and with or without anti-CMV CDR3s; median survival of seropositive cases (n = 53) (black), 32 months; median survival of seronegative cases (n = 79) (grey), 82 months. Log-rank p value, 1.074e-4. N-proportion test p value = 0.0001 at 154 months. B Case IDs with MYCN amplification and with or without anti-viral CDR3s; median survival of seropositive cases (n = 28) (black), 18 months; median survival of seronegative (n = 36) (grey), 43 months. Log-rank p value, 0.0576. N-proportion test p value, 0.0721 at 63 months

Fig. 2

KM OS analysis of case IDs positive for anti-CMV CDR3s and MYCN amplification. Case IDs positive for anti-CMV CDR3s and MYCN amplification (black, n = 28; median survival, 18 months); case IDs negative for anti-CMV CDR3s and without MYCN amplification (grey, n = 79; median survival, 82 months). Log-rank p value = 9.804e-5. N-proportion test p value = 0.0004 at 40 months

Fig. 3

KM OS analyses representing case IDs grouped into upper and lower 50th percentile groups for TRB CDR3-CMV pp65 peptide fragment CSs. A Case IDs representing the upper 50th percentile of CSs for blood-sourced, TRB CDR3s and pp65 fragment MESRGRRCPEMISVLGPISGHVLKAVFSRGDTPVLPHETRLLQTGIH combinations (black, n = 105; median survival, 31 months) and case IDs representing the lower 50th percentile of the CSs (grey, n = 75; median survival, NA). B Case IDs representing the upper 50th percentile of CSs for blood-sourced, TRB CDR3s and pp65 fragment AVIHASGKQMWQARLTVSGLAWTRQQNQWKEPDVYYTS combinations (black, n = 92; median survival, 31 months) and case IDs representing the lower 50th percentile of the CSs (grey, n = 88; median survival, 73 months). C Case IDs representing the upper 50th percentile of CSs for blood-sourced, TRB CDR3s and pp65 fragment AIRETVELRQYDPVAALFFFDIDLLLQRGPQYS combinations (black, n = 91; median survival, 37 months) and case IDs representing the lower 50th percentile of the CSs (grey, n = 89; median survival, 46 months)