D-2-hydroxyglutarate supports a tolerogenic phenotype with lowered major histocompatibility class II expression in non-malignant dendritic cells and acute myeloid leukemia cells.
Kathrin Hammon, Kathrin Renner, Michael Althammer, Florian Voll, Nathalie Babl, Sonja-Maria Decking, Peter J Siska, Carina Matos, Zugey Elizabeth Cárdenas Conejo, Karina Mendes, Friederike Einwag, Heiko Siegmund, Sabine Iberl, Raffaela S Berger, Katja Dettmer, Rebecca Schoenmehl, Christoph Brochhausen, Wolfgang Herr, Peter J Oefner, Michael Rehli, Simone Thomas, Marina Kreutz
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引用次数: 0
Abstract
D-2-hydroxyglutarate (D-2-HG) accumulates in patients with acute myeloid leukemia (AML) with mutated isocitrate dehydrogenase (IDH) and in other malignancies. D-2-HG suppresses antitumor T-cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell differentiation, resulting in a tolerogenic phenotype with low major histocompatibility class II expression. In line with this, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, besides its expected impact on DNA demethylation, D-2-HG reprogrammed metabolism towards increased lactate production in dendritic cells and AML. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported major histocompatibility complex class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.
D-2-羟基戊二酸支持耐受表型,降低了非恶性树突状细胞和急性髓性白血病细胞中主要组织相容性 II 类的表达。
在异柠檬酸脱氢酶(IDH)突变的原发性急性髓性白血病(AML)患者和其他恶性肿瘤患者体内,D-2-羟基戊二酸(D-2-HG)会累积。D-2-HG 可抑制抗肿瘤 T 细胞免疫,但对非恶性髓系细胞的潜在影响却知之甚少。我们在这里发现,D-2-HG 会影响人类树突状细胞(DC)的分化,但不会影响鼠类树突状细胞的分化,从而导致主要组织相容性(MHC)II 类低表达的耐受表型。同样,IDH突变的急性髓细胞白细胞表现出较低的HLA-DP表达,并且不易被HLA-DP特异性T细胞溶解。有趣的是,D-2-HG 除了对 DNA 去甲基化产生预期的影响外,还对 DCs 和 AML 的新陈代谢进行了重编程,使乳酸生成增加。维生素 C 加速了 DNA 的去甲基化,但只有维生素 C 和糖酵解抑制的结合才能降低乳酸水平并支持 MHC II 类表达。我们的研究结果表明,免疫抑制代谢物2-HG与乳酸之间存在着意想不到的联系,并提出了一种潜在的新型治疗策略,即结合使用抗糖酵解药物和表观遗传调节剂(低甲基化药物)或其他治疗药物来治疗急性髓细胞白血病。
期刊介绍:
Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research.
Scope:
The scope of the journal includes reporting novel research results that:
Have a significant impact on understanding normal hematology or the development of hematological diseases.
Are likely to bring important changes to the diagnosis or treatment of hematological diseases.