Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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.
过继性 T 细胞疗法是癌症患者有前途的治疗方法。只要控制固有异基因反应，使用同种异体 T 细胞移植物将提高其适用性和通用性。T 细胞的激活受到多种信号分子的精细调节，这些信号分子受表观遗传机制转录调控。在这里，我们报告抑制组蛋白 H3-赖氨酸 79 甲基转移酶 DOT1L 可减轻同种异体 T 细胞反应。DOT1L 抑制降低了 miR-181a 的表达，进而增加了 ERK 磷酸酶 DUSP6 的表达，并通过全局抑制 T 细胞激活诱导的基因表达改变选择性改善低亲和力 T 细胞反应。T 细胞中 DOT1L 的抑制或 DUSP6 的过表达可减轻移植物抗宿主病的发展，同时在异种和同种异体过继免疫治疗模型中保留有效的抗肿瘤活性。这些结果表明，通过抑制过继免疫治疗中的不必要免疫反应，DOT1L 抑制可能使安全有效地使用同种异体抗肿瘤 T 细胞成为可能。
