Abstract A101: IDO2 host genetic status influences progression and radiotherapy response in pancreatic ductal adenocarcinoma

Abstract

Sporadic pancreatic ductal adenocarcinoma (PDAC) develops into a lethal disease that has remained refractory to different treatment approaches including recent advances in cancer immunotherapy. Variations in host genetic status affecting the inflammatory microenvironment can impact cancer susceptibility, malignant progression and clinical outcomes. In this study, we present genetic evidence from mouse and human genetic studies supporting a role for IDO2, an immunometabolic modifier of B cell-mediated autoimmune responses, in promoting pancreatic ductal adenocarcinoma (PDAC). In an established transgenic mouse model of KRAS-induced pancreatic cancer, IDO2 genetic inactivation markedly reduced malignant progression. In retrospective clinical analyses of PDAC patients (N=200), the biallelic occurrence of either of two inactivating polymorphisms in the IDO2 coding region trended with favorable disease-free survival. In PDAC tissues, an inactive IDO2 host genotype corresponded with changes in expression of genes involved in tryptophan catabolism and immune modulation, along with a reduced neutrophil to lymphocyte ratio. Notably, subset analysis revealed a striking association of inactive IDO2 status with improved disease-free survival in patients who had received adjuvant radiotherapy, a treatment modality that has been highly debated due to its variable efficacy in patients. Accordingly, our findings suggest that host IDO2 genetic status may offer a simple incisive marker to stratify PDAC patients who stand to gain the most from adjuvant radiotherapy, addressing the long-standing debate of its benefits. Citation Format: George C. Prendergast, Avinoam Nevler, Alexander J. Muller, Erika Sutanto-Ward, James B. DuHadaway, Kei Nagatomo, Eric Londin, Kevin O9Hayer, Joseph A. Cozzitorto, Harish Lavu, Theresa P. Yeo, Mark Curtis, Tatiana Villatoro, Benjamin E. Leiby, Jordan M. Winter, Charles J. Yeo, Jonathan R. Brody. IDO2 host genetic status influences progression and radiotherapy response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A101.