High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia

Mabuchi, Ryoko; Hara, Takeshi; Matsumoto, Tomohiro; Shibata, Yuhei; Nakamura, Nobuhiko; Nakamura, Hiroshi; Kitagawa, Junichi; Kanemura, Nobuhiro; Goto, Naoe; Shimizu, Masahito; Ito, Hiroyasu; Yamamoto, Yorimasa; Saito, Kuniaki; Moriwaki, Hisataka; Tsurumi, Hisashi

doi:10.3109/10428194.2015.1041388

Cited by 35 publications

(33 citation statements)

References 47 publications

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“…Recently it was reported that galectin-9 induces interferon-gamma (IFN-γ) release from NK cells ( Gleason et al, 2012 ). IFN-γ interacts with AML cells inducing the activity of indoleamine 2,3-dioxygenase (IDO1), an enzyme which converts L-tryptophan into formyl-L-kynurenine, which is then converted into L-kynurenine and released ( Corm et al, 2009 , Folgiero et al, 2015 , Mabuchi et al, 2016 ). L-kynurenine affects the ability of NK cells to kill AML cells, an effect which was seen in our experiments and presented in Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

et al. 2017

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Acute myeloid leukemia (AML) is a severe and often fatal systemic malignancy. Malignant cells are capable of escaping host immune surveillance by inactivating cytotoxic lymphoid cells. In this work we discovered a fundamental molecular pathway, which includes ligand-dependent activation of ectopically expressed latrophilin 1 and possibly other G-protein coupled receptors leading to increased translation and exocytosis of the immune receptor Tim-3 and its ligand galectin-9. This occurs in a protein kinase C and mTOR (mammalian target of rapamycin)-dependent manner. Tim-3 participates in galectin-9 secretion and is also released in a free soluble form. Galectin-9 impairs the anti-cancer activity of cytotoxic lymphoid cells including natural killer (NK) cells. Soluble Tim-3 prevents secretion of interleukin-2 (IL-2) required for the activation of cytotoxic lymphoid cells. These results were validated in ex vivo experiments using primary samples from AML patients. This pathway provides reliable targets for both highly specific diagnosis and immune therapy of AML.

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Section: Discussionmentioning

confidence: 99%

The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

et al. 2017

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“…There is some evidence pointing to a potential role for IDO in AML. First, elevated systemic levels of kynurenine are detectable in patients with AML and have been shown to negatively correlate with overall survival in patients with intermediate risk disease ( 62 , 63 ). IDO has been measured directly in AML blasts both constitutively and after exposure to IFNγ, indicating that the tumor itself may be responsible for the observed systemic kynurenine levels ( 64 , 65 ).…”

Section: Mechanisms Of T Cell Dysfunction In Amlmentioning

confidence: 99%

Targeting the Immune Microenvironment in Acute Myeloid Leukemia: A Focus on T Cell Immunity

2018

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Immunotherapies, such as chimeric antigen receptor T cells, bispecific antibodies, and immune checkpoint inhibitors, have emerged as promising modalities in multiple hematologic malignancies. Despite the excitement surrounding immunotherapy, it is currently not possible to predict which patients will respond. Within solid tumors, the status of the immune microenvironment provides valuable insight regarding potential responses to immune therapies. Much less is known about the immune microenvironment within hematologic malignancies but the characteristics of this environment are likely to serve a similar predictive role. Acute myeloid leukemia (AML) is the most common hematologic malignancy in adults, and only 25% of patients are alive 5 years following their diagnosis. There is evidence that manipulation of the immune microenvironment by leukemia cells may play a role in promoting therapy resistance and disease relapse. In addition, it has long been documented that through modulation of the immune system following allogeneic bone marrow transplant, AML can be cured, even in patients with the highest risk disease. These concepts, along with the poor prognosis associated with this disease, have encouraged many groups to start exploring the utility of novel immune therapies in AML. While the implementation of these therapies into clinical trials for AML has been supported by preclinical rationale, many questions still exist surrounding their efficacy, tolerability, and the overall optimal approach. In this review, we discuss what is known about the immune microenvironment within AML with a specific focus on T cells and checkpoints, along with their implications for immune therapies.

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“…IDO overexpression is correlated with poor clinical outcome in patients with ovarian, endometrial, and colorectal carcinomas [ 13 , 14 ]. We have previously reported that IDO expression in tumor cells and the serum concentration of kynurenine in patients with diffuse large B-cell lymphoma [ 15 – 17 ], or with acute myeloid leukemia [ 18 , 19 ] are useful prognostic factors. On the other hand, several preclinical studies have demonstrated that IDO inhibitors, such as 1-methyl-tryptophan (1-MT), are therapeutically beneficial for inhibition of cancer cell growth, especially when they are combined with different types of cytotoxic chemotherapeutic agents [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

et al. 2016

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.

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High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia

Cited by 35 publications

References 47 publications

The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells

Targeting the Immune Microenvironment in Acute Myeloid Leukemia: A Focus on T Cell Immunity

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

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