Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers

Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately impact cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2in humans is the high prevalence of two inactivating single nucleotide polymorphisms (SNPs) which affords the opportunity to carry out loss-of-function studies directly in humans. In this study we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment. Experimental Design: Transgenic Ido2^+/+and Ido2^-/-micein which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient datasets (N=200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression and clinical survival data. Results: PDAC development was notably decreased in the Ido2^-/- mice (30% vs 10%, P<0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P<0.01), a treatment modality that has been highly debated due to its variable efficacy. Conclusions: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.

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