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

Yuki Kagoya, Munehide Nakatsugawa, Kayoko Saso, Tingxi Guo, Mark Anczurowski, Chung-Hsi Wang, Marcus O. Butler, Cheryl H. Arrowsmith and Naoto Hirano ()
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Yuki Kagoya: University Health Network
Munehide Nakatsugawa: University Health Network
Kayoko Saso: University Health Network
Tingxi Guo: University Health Network
Mark Anczurowski: University Health Network
Chung-Hsi Wang: University Health Network
Marcus O. Butler: University Health Network
Cheryl H. Arrowsmith: University of Toronto
Naoto Hirano: University Health Network

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04262-0

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