Gene expression analysis of human CD8+ T cells treated with a DOT1L inhibitor

Adoptive T cell therapy (ACT) 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. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition with SGC0946 selectively ameliorated low-avidity T cell responses but not high-avidity antitumor T cell responses mediated by the high-affinity T cell receptor or chimeric antigen receptor. The inhibition of DOT1L in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in xenogeneic ACT 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 ACT. Overall design: To investigate how DOT1L inhibition modulates the T cell activation signal, we compared gene expression profiles between SGC0946-treated or DMSO-treated (control) T cells by RNA-sequencing analysis. Human CD8+ T cells derived from three different healthy donors were cultured in the presence of SGC0946 or DMSO. Total RNA was collected from each sample and gene expression profiles were analyzed by RNA-sequencing using an Illumina HiSeq 2500 sequencer.

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Kagoya Y, Nakatsugawa M, Saso K, Guo T, Anczurowski M, Wang CH, Butler MO, Arrowsmith CH, Hirano N