Genotyping and Expression Analysis of IDO2 in Human Pancreatic Cancer: A Novel, Active Target

Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Journal of the American College of Surgeons (Impact Factor: 5.12). 06/2009; 208(5):781-7; discussion 787-9. DOI: 10.1016/j.jamcollsurg.2008.12.018
Source: PubMed

ABSTRACT The recently discovered indoleamine 2,3-dioxygenase-2 (IDO2) gene has 2 functional polymorphisms that abolish its enzymatic activity. We hypothesize that expression of the IDO2 enzyme in primary pancreatic ductal adenocarcinomas (PDA) can help cancer cells evade immune detection.
Because the IDO2 enzyme might be the preferential target of d-1-methyl-tryptophan, a clinical lead inhibitor of IDO currently being evaluated in phase I trials, we sequenced IDO2 in 36 pancreatic specimens and evaluated its expression.
We found that 58% (21 of 36) of cases were heterozygous for the R248W polymorphism; 28% (10 of 36) were homozygous wild-type; and only 14% (5 of 36) were homozygous for the functionally inactive polymorphism. As for the Y359STOP polymorphism, we found that 27% (10 of 36) of cases were heterozygous, 62% (22 of 36) were homozygous wild-type, and only 11% (4 of 36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75% of our resected patient cohort had an active IDO2 enzyme, with a conservative estimate that 58% of the patients had at least 1 functional allele. IDO2 was expressed in PDA tissue from each genetically polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with interferon-gamma.
This is the first study to report IDO2 expression in PDA and related cancers indicating that IDO2 genetic polymorphisms do not negate interferon-gamma-inducible protein expression. Taken together, our data strongly suggest that the clinical lead compound d-1-methyl-tryptophan might be useful in treatment of PDA.

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Available from: George C Prendergast, Sep 25, 2015
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    • "Expression of IDO2 mRNA has been described in kidney, liver, epididymis, testis, uterus, placenta, and brain (15, 38, 43). IDO2 has also been found in sperm tails (38), pancreatic cancer cell lines (44), and tumors of the stomach, colon, and kidney (45). Similar to IDO1, IFN-γ upregulates IDO2 expression in DC (45), mesenchymal stem cells, macrophages, and astrocytes (43), although IFN-γ does not necessarily induce IDO1 and IDO2 simultaneously (19, 43). "
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    ABSTRACT: This review discusses the mechanisms and consequences of degradation of tryptophan (Trp) in the placenta, focusing mainly on the role of indoleamine 2,3-dioxygenase-1 (IDO1), one of three enzymes catalyzing the first step of the kynurenine pathway of Trp degradation. IDO1 has been implicated in regulation of feto-maternal tolerance in the mouse. Local depletion of Trp and/or the presence of metabolites of the kynurenine pathway mediate immunoregulation and exert antimicrobial functions. In addition to the decidual glandular epithelium, IDO1 is localized in the vascular endothelium of the villous chorion and also in the endothelium of spiral arteries of the decidua. Possible consequences of IDO1-mediated catabolism of Trp in the endothelium encompass antimicrobial activity and immunosuppression, as well as relaxation of the placental vasotonus, thereby contributing to placental perfusion and growth of both placenta and fetus. It remains to be evaluated whether other enzymes mediating Trp oxidation, such as indoleamine 2,3-dioxygenase-2, Trp 2,3-dioxygenase, and Trp hydroxylase-1 are of relevance to the biology of the placenta.
    Frontiers in Immunology 05/2014; 5:230. DOI:10.3389/fimmu.2014.00230
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    • "As already mentioned Treg may play a role in inhibiting CD8 T cell responses by various mechanisms [22], and MDSC and other cells on the innate immune system may play a similar role [28, 69, 76, 93]. For instance, expression of the enzymes Indoleamine-2,3-dioxygenase 1 (IDO-1) [72], IDO-2 or tryptophan 2,3-dioxygenase (TDO) [114], or tryptophan hydroxylase-1 [75] all metabolize tryptophan and thereby deplete Trp in the microenvironment. These enzymes may be expressed by cancer cells or by cells of the innate immune system; e.g. "
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    ABSTRACT: T cells in tumors-the so-called tumor infiltrating lymphocytes (TIL) have been studied intensively over the past years. Compelling evidence point to a clinical relevance for high numbers of T cells at the tumor site with CD8 memory T cells as a key denominator for overall survival (OS) in patients with colo-rectal cancer (CRC), and also for others solid cancers. These data goes hand in hand with studies of clonality of TIL showing the T cells among TIL are expanded clonally, and also that tumor specific T cells of CD4 as well as CD8 type are enriched at the tumor site. The tumor microenvironment is hostile to T cell function e.g., due to expression of enzymes that depletes the amino acids tryptophan and arginine, high concentration of tumor secreted lactate, and presence innate cells or regulatory T cells both with suppressive activity. Analyses of the specificity of TILs in melanoma demonstrate that quite few known antigens are in fact recognized by these cultures underscoring patient unique and/or mutated antigens may represent important target for recognition.
    Cancer Microenvironment 12/2012; 6(2). DOI:10.1007/s12307-012-0127-6
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    • "First, IDO2 expression has been described in human tumors, including renal and pancreatic tumors. In pancreatic tumors IDO2 expression was described both at the level of the tumor cell as well as immune cells in tumor-draining lymph nodes.10 Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1MT, which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors.8 "
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    ABSTRACT: Two frequent single-nucleotide-polymorphisms (SNPs) are present in the indoleamine 2,3-dioxygenase 2 (IDO2) gene that influence its enzymatic activity. Thus, one SNP (R248W) is associated with a reduction in IDO2 catalytic activity, whereas the other SNP (Y359stop) generates a premature stop codon abolishing activity completely. In the present study, we describe the presence of a specific cellular immune response in the periphery which correlated with the functional status of the IDO2 protein. Hence, the induction of IDO2-specific T cells in peripheral blood requires the presence of a functional IDO2 protein and, consequently, is restricted to individuals that are not homozygous for the stop codon. Furthermore, we detected stronger T-cell responses in donors with the homozygous Y wild type at position 359 when compared with the heterozygous genotype. Interestingly, we found a higher number of immune responses against IDO2 in patients homozygous for the 248W giving reduction in IDO2 activity compared with the 248R. Hence, spontaneous immune responses against IDO2 seem to be correlated with reduced enzymatic activity of IDO2. The patient IDO2 genotype may well influence the outcome of IDO2-based anti-cancer vaccination.
    OncoImmunology 07/2012; 1(4):441-447. DOI:10.4161/onci.19654 · 6.27 Impact Factor
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