Time series clustering of T cell subsets dissects heterogeneity in immune reconstitution and clinical outcomes among MUD-HCT patients receiving ATG or PTCy

Frontiers in Immunology

Immunology

Martina Franke¹  Nils Leimkühler¹  Ulrike Buttkereit¹  Dietrich W. Beelen¹  Hans Christian Reinhardt²  Theresa Graf³  Rashit Bogdanov³  Amin T. Turki⁴  Saskia Leserer⁴  Katharina Fleischhauer⁵  Esteban Arrieta-Bolaños⁵ 

[1] Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Cancer Research Center Cologne Essen (CCCE), Essen, Germany;Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Computational Hematology Lab, Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Computational Hematology Lab, Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany;Institute for Experimental Cellular Therapy, West-German Cancer Center, University Hospital Essen, Essen, Germany;Institute for Experimental Cellular Therapy, West-German Cancer Center, University Hospital Essen, Essen, Germany;German Cancer Consortium Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner site Essen/Düsseldorf, Essen, Germany;

关键词: GVHD prophylaxis;    anti-thymocyte globulin (ATG);    post-transplant cyclophosphamide;    unsupervised learning;    matched unrelated donor allogeneic hematopoietic stem cell transplantation;    anti-T-lymphocyte globulin;    time-series (TS) model;    dynamic time warping (DTW);   

DOI  :  10.3389/fimmu.2023.1082727

 received in 2022-10-28, accepted in 2023-03-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAnti-T-lymphocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy) prevent graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT), yet individual patients benefit differentially.MethodsGiven the sparse comparative data on the impact of cellular immune reconstitution in this setting, we studied flow cytometry and clinical outcomes in 339 recipients of 10/10 matched-unrelated donor (MUD) HCT using either ATG (n=304) or PTCy (n=35) for in vivo T cell manipulation along with a haploidentical PTCy control cohort (n=45). Longitudinal cellular immune reconstitution data were analyzed conventionally and with a data science approach using clustering with dynamic time warping to determine the similarity between time-series of T cell subsets.ResultsConsistent with published studies, no significant differences in clinical outcomes were observed at the cohort level between MUD-ATG and MUD-PTCy. However, cellular reconstitution revealed preferences for distinct T cell subpopulations associating with GVHD protection in each setting. Starting early after HCT, MUD-PTCy patients had higher regulatory T cell levels after HCT (p <0.0001), while MUD-ATG patients presented with higher levels of γδ T- or NKT cells (both p <0.0001). Time-series clustering further dissected the patient population’s heterogeneity revealing distinct immune reconstitution clusters. Importantly, it identified phenotypes that reproducibly associated with impaired clinical outcomes within the same in vivo T cell manipulation platform. Exemplarily, patients with lower activated- and αβ T cell counts had significantly higher NRM (p=0.032) and relapse rates (p =0.01).DiscussionThe improved understanding of the heterogeneity of cellular reconstitution in MUD patients with T cell manipulation both at the cohort and individual level may support clinicians in managing HCT complications.

【 授权许可】

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Copyright © 2023 Leserer, Graf, Franke, Bogdanov, Arrieta-Bolaños, Buttkereit, Leimkühler, Fleischhauer, Reinhardt, Beelen and Turki