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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allogeneic Cells / immunology*
  • Animals
  • Disease Models, Animal
  • Female
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / therapy*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Immunotherapy, Adoptive*
  • Lymphocyte Activation
  • Male
  • Methyltransferases / genetics
  • Methyltransferases / immunology*
  • Mice, Inbred BALB C
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • T-Lymphocytes / immunology*


  • MicroRNAs
  • mirn181 microRNA, mouse
  • Dot1l protein, mouse
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase