Öztürk Selcen, Kalter Verena, Roessner Philipp M, Sunbul Murat, Seiffert Martina
Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany.
Cancers (Basel). 2021 Apr 15;13(8):1899. doi: 10.3390/cancers13081899.
Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.
吲哚胺-2,3-双加氧酶1（IDO1）是一种分解色氨酸（Trp）的酶，可产生犬尿氨酸（Kyn）等代谢产物，由髓系来源的抑制性细胞（MDSCs）表达，并与癌症免疫逃逸相关。研究表明，表达IDO1的单核细胞MDSCs在慢性淋巴细胞白血病（CLL）患者中积聚，并在体外抑制T细胞活性并诱导抑制性调节性T细胞（Tregs）。在CLL的Eµ-TCL1小鼠模型中，我们观察到单核细胞和粒细胞MDSCs中IDO1强烈上调，并且血清中犬尿氨酸与色氨酸的比率显著增加。为了探索IDO1作为CLL治疗靶点的潜力，我们在用Eµ-TCL1白血病细胞过继转移后的小鼠中用IDO1调节剂1-甲基-D-色氨酸（1-MT）进行治疗，这导致白血病发展略有减少，但随着时间的推移这种减少消失了。1-MT治疗还部分挽救了由CLL发展诱导的免疫细胞变化。同样，用临床研究的IDO1抑制剂依帕司他治疗白血病小鼠可降低Tregs的频率，并最初略微延迟CLL的发展，然而，这种效果在后期时间点消失了。总之，尽管在CLL中观察到IDO1上调，但其抑制不足以在Eµ-TCL1过继转移模型中控制白血病的发展。
