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Nat Commun. 2018 May 15;9(1):1915. doi: 10.1038/s41467-018-04262-0.

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

Author information

1
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
2
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
3
Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
4
Structural Genomics Consortium and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
6
Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada. naoto.hirano@uhnresearch.ca.
7
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada. naoto.hirano@uhnresearch.ca.

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.

PMID:
29765028
PMCID:
PMC5954061
DOI:
10.1038/s41467-018-04262-0
[Indexed for MEDLINE]
Free PMC Article

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