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Expression analysis of CD8+ T cells following high-avidity or low-avidity T cell receptor (TCR) stimulation in the presence or absence of a DOT1L inhibitor

ABSTRACT: 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. T cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition reduced miR-181a expression, which increased the ERK phosphatase DUSP6 expression. The inhibition of DOT1L or ectopic expression of DUSP6 in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in multiple 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. To further explore how DOT1L inhibition differentially affects high- and low-avidity stimulation-mediated T cell responses, gene expression profiles of DMF5- (high affinity) or cl.413- (low affinity) TCR-transduced T cells with or without SGC0946 treatment were analyzed following TCR stimulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95038 | GEO | 2018/04/20

REPOSITORIES: GEO

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

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