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


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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    • "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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    • "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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