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T cell receptor beta locus sequencing early post-allogeneic stem cell transplant identifies patients at risk of initial and recurrent cytomegalovirus infection

Abstract

Identification of patients at risk of initial & recurrent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant (alloSCT) may help guide prophylactic strategies. T-cell receptor beta (TRB) deep sequencing was used to identify and enumerate the T-cell repertoire harbouring TRB sequences with annotated specificity to CMV (pubCMVrep), as well as the overall T-cell receptor (TCR) repertoire diversity at day +30 & day +60 post-alloSCT for 65 patients. T-cells harbouring TRB sequences with annotated specificity for CMV were identifiable in all patients. 56% of patients required CMV treatment and 23% of the cohort developed recurrent CMV. PubCMVrep size at day +30 was not associated with reactivation, however amongst patients with antecedent CMV viremia a low day +60 pubCMVrep was associated with a greater incidence of recurrent CMV (75% vs. 21%, HR 6.16, 95% CI 1.29–29.40, P = 0.0008). Moreover, patients with high pubCMVrep only developed recurrent CMV in the setting of GVHD. Low TCR diversity at day +30 was associated with a greater incidence of initial CMV reactivation (71% vs. 22%, HR 5.39, 95% CI 1.70–17.09, p = 0.0002). pubCMVrep and TCR diversity are promising biomarkers to identify patients at risk of initial & recurrent CMV who may benefit from novel prophylactic strategies.

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Fig. 1: Public CMV repertoire (pubCMVrep) for all patients at day +30 and day +60 post-alloSCT & impact of serostatus on pubCMVrep.
Fig. 2: Association between overall T cell receptor (TCR) diversity and cumulative incidence of initial CMV treatment.
Fig. 3: Impact of pubCMVrep on incidence of recurrent CMV.
Fig. 4: Schematic diagram of proposed contributions of pre-transplant factors, early post-transplant T cell receptor (TCR) repertoire diversity and public CMV-specific T-cell repertoire (pubCMVrep) on initial and recurrent CMV infection.

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Acknowledgements

This work was supported by grants from the Wilson Centre for Lymphoma Genomics and the Snowdome Foundation.

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Correspondence to James A. Kuzich.

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Kuzich, J.A., Kankanige, Y., Guinto, J. et al. T cell receptor beta locus sequencing early post-allogeneic stem cell transplant identifies patients at risk of initial and recurrent cytomegalovirus infection. Bone Marrow Transplant 56, 2582–2590 (2021). https://doi.org/10.1038/s41409-021-01354-2

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