TY - JOUR
T1 - DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models
AU - Kagoya, Yuki
AU - Nakatsugawa, Munehide
AU - Saso, Kayoko
AU - Guo, Tingxi
AU - Anczurowski, Mark
AU - Wang, Chung Hsi
AU - Butler, Marcus O.
AU - Arrowsmith, Cheryl H.
AU - Hirano, Naoto
N1 - Funding Information:
This work was supported by Ontario Institute for Cancer Research Clinical Investigator Award IA-039 (N.H.); the Princess Margaret Cancer Foundation (MOB, N.H.); Medicine by Design: A Canada First Research Excellence Fund Program at the University of Toronto (N.H.); the Japan Society for the Promotion of Science Postdoctoral Fellowship for Overseas Researchers (Y.K.); Guglietti Fellowship Award (Y.K.); the Canadian Institutes of Health Research Canada Graduate Scholarship (T.G.); Province of Ontario (T.G., M.A.); and the Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship (T.G.). The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-04262-0
DO - 10.1038/s41467-018-04262-0
M3 - Article
C2 - 29765028
AN - SCOPUS:85047071143
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1915
ER -
