DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models

Nature Communications
Yuki KagoyaNaoto Hirano

Abstract

Adoptive T-cell therapy is a promising therapeutic approach for cancer patients. The use of allogeneic T-cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T-cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Here we report that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviates allogeneic T-cell responses. DOT1L inhibition reduces miR-181a expression, which in turn increases the ERK phosphatase DUSP6 expression and selectively ameliorates low-avidity T-cell responses through globally suppressing T-cell activation-induced gene expression alterations. The inhibition of DOT1L or DUSP6 overexpression in T cells attenuates the development of graft-versus-host disease, while retaining potent antitumor activity in xenogeneic and allogeneic adoptive immunotherapy models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in adoptive immunotherapy.

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Citations

Aug 23, 2019·The Journal of Experimental Medicine·Benyu LiuZusen Fan
Aug 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Eliza Mari Kwesi-MaliepaardHeinz Jacobs
Jan 27, 2021·Cellular and Molecular Gastroenterology and Hepatology·Wanlin YangWei Cai
Apr 20, 2021·Trends in Immunology·Heleen H Van AckerMassimiliano Mazzone

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Datasets Mentioned

BETA
GSE13887
GSE95038

Methods Mentioned

BETA
flow cytometry
bioluminescence imaging
genetic knockout
density gradient centrifugation
PMA
enzyme-linked
ELISA
PCR
Assay

Clinical Trials Mentioned

NCT01684150

Software Mentioned

FASTX Toolkit
TopHat
FlowJo
HeatPlus
GraphPad Prism
ggplot2
Affymetrix Expression Console
Bioconductor
Tree Star
R package “ stats ”

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