T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response
Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna
Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna
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Clinical Research and Public Health Immunology

T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response

Abstract

BACKGROUND Impaired T cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.METHODS In the present study, we used high-throughput T cell receptor Vβ sequencing and T cell functional profiling to delineate the impact of ACT on T cell repertoire remodeling in the context of pretherapy immunity and ACT products.RESULTS These analyses indicated that a clinical response was coincident with significant changes in the T cell receptor Vβ landscape after therapy. This restructuring was associated with the emergence of effector memory T cells in responding patients, while nonresponders displayed dramatic pretherapy T cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products.CONCLUSION These observations demonstrate that immune control following ACT requires significant repertoire remodeling, which may be impaired in nonresponders because of the preexisting immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.TRIAL REGISTRATION Australian New Zealand Clinical Trial Registry, ACTRN12613000981729.FUNDING This study was supported by funding from the National Health and Medical Research Council, Australia (APP1132519 and APP1062074).

Authors

Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna

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Figure 3

Changes in the clonotypic composition of the peripheral blood CD8+ T cell repertoire following adoptive immunotherapy.

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Changes in the clonotypic composition of the peripheral blood CD8+ T cel...
Significant changes in the frequency of patient CD8+ T cell clonotypes following adoptive cellular therapy were determined using the immunoSEQ platform. Significance was assessed in CDR3 sequences with a minimum of 5 reads. Significance was determined using a 2-sided binomial test with Benjamini-Hochberg multiple-comparisons correction, where α = 0.01. (A) Representative analyses from 3 patients comparing the frequency of T cell clonotypes in preinfusion and long-term post-therapy blood samples. Significantly expanded clonotypes post-therapy are shown in red. Clonotypes that show a significant reduction post-therapy are shown in blue. (B) Data represent the number of clonotypes in each patient that displayed significant expansion post-therapy. (C) The frequencies of TRBV families detected in significantly expanded clonotypes from each patient, represented as a proportion of the total CD8+ T cell population. (D) GLIPH analysis was performed to determine the relationship between expanded clonotypes. Data represent CDR3 motifs enriched after immunotherapy in 3 responding patients.