Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

F Milano; R O Emerson; R Salit; K A Guthrie; L A Thur; A Dahlberg; H S Robins; C Delaney

doi:10.3389/fonc.2020.583349

Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation

Front Oncol. 2020 Oct 9:10:583349. doi: 10.3389/fonc.2020.583349. eCollection 2020.

Authors

F Milano^{1

2}, R O Emerson³, R Salit^{1

2}, K A Guthrie¹, L A Thur¹, A Dahlberg^{1

4}, H S Robins^{1

3}, C Delaney^{1

4}

Affiliations

¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
² Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
³ Adaptive Biotechnologies, Seattle, WA, United States.
⁴ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States.

Abstract

Introduction: Cord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.

Methods: All patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.

Results: Median age was 27 (range 1-58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).

Conclusions: Using a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.

Keywords: T-cell receptor sequencing; T-cell repertoire diversity; cord blood transplantation; delayed immune recovery; immune reconstitution.