Culture expansion of CAR T cells results in aberrant DNA methylation that is associated with adverse clinical outcome

Author:

Salz LuciaORCID,Seitz Alexander,Schäfer Daniel,Franzen JuliaORCID,Holzer Tatjana,Garcia-Prieto Carlos A.,Bürger Iris,Hardt Olaf,Esteller ManelORCID,Wagner WolfgangORCID

Abstract

AbstractChimeric antigen receptor (CAR) T cells provide new perspectives for treatment of hematological malignancies. Manufacturing of these cellular products includes culture expansion procedures, which may affect cellular integrity and therapeutic outcome. In this study, we investigated culture-associated epigenetic changes in CAR T cells and found continuous gain of DNAm, particularly within genes that are relevant for T cell function. Hypermethylation in many genes, such as TCF7, RUNX1, and TOX, was reflected by transcriptional downregulation. 332 CG dinucleotides (CpGs) showed an almost linear gain in methylation with cell culture time, albeit neighboring CpGs were not coherently regulated on the same DNA strands. An epigenetic signature based on 14 of these culture-associated CpGs predicted cell culture time across various culture conditions. Notably, even in CAR T cell products of similar culture time higher DNAm levels at these CpGs were associated with significantly reduced long-term survival post transfusion. Our data demonstrate that cell culture expansion of CAR T cells evokes DNA hypermethylation at specific sites in the genome and the signature may also reflect loss of potential in CAR T cell products. Hence, reduced cultivation periods are beneficial to avoid dysfunctional methylation programs that seem to be associated with worse therapeutic outcome.

Funder

Deutsche Forschungsgemeinschaft

Else Kröner-Fresenius-Stiftung

Generalitat de Catalunya

European Commission

Consell Català de Recerca i Innovació

Fundación Cellex

Publisher

Springer Science and Business Media LLC

Subject

Oncology,Cancer Research,Hematology

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