INTRODUCTION: Indolamine 2,3-dioxygenase 1 (IDO1) is upregulated in tumors. It facilitates catabolism of tryptophan to kynurenine and downstream metabolites, which are associated with psychiatric symptoms. To this point, 20% of patients at our institution developed psychiatric symptoms months before pancreatic cancer (PC) diagnosis. This proportion was threefold greater relative to non-cancer controls (6.7%), supplying indirect evidence of a biochemical link. Herein, we investigate IDO1 as a target in pancreatic cancer-associated depression.

METHODS: Human and murine PC cells were used in vitro. Protein levels were assessed using western blotting and cell survival by PicoGreen. For in vivo studies, murine PC cells were injected into the pancreatic tail. Control mice underwent an acellular injection. Mice were treated with epacadostat (an IDO1 inhibitor), escitalopram, or vehicle. To evaluate depressive-like behavior, mice were subjected to the forced swim and tail suspension tests. The open field test was used to monitor mobility. Tumors were analyzed using western blotting and serum metabolites were assessed using LC-MS.

RESULTS: Murine and human PC cells had undetectable basal IDO1 protein levels; however, there was a strong induction with interferon-gamma. There was a further increase in IDO1 with added epacadostat. Escitalopram had no effect on IDO1 levels. Epacadostat and escitalopram did not impact PC cell viability. Physical mobility of PC mice was similar to controls over the study period. PC mice were more immobile relative to controls during the forced swim (percent immobile: 16.0% v 8.2%, p<0.001) and tail suspension (24.1% v 15.4%, p=0.003) tests. There was a 2.3-fold increase in serum kynurenine levels in PC mice relative to controls (p<0.001).PC mice treated with epacadostat were less immobile relative to PC mice receiving vehicle in both the forced swim (3.2% v 6.6%, p=0.002) and tail suspension (25.0% v 39.3%, p=0.002) tests. Metabolomics demonstrated a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to vehicle (p<0.001). Tumors of mice treated with epacadostat exhibited a compensatory upregulation of IDO1. Mice treated with escitalopram performed similarly to vehicle-treated mice on the forced swim (7.6%, p=0.85) and tail suspension (38.7%, p=0.77) tests, and kynurenine levels were similar. CONCLUSION: Mice with PC exhibit depressive-like behavior relative to control mice with an associated increase in kynurenine. Treatment with epacadostat improved depressive-like behavior and dramatically reduced kynurenine. These data provide evidence to trial epacadostat in patients battling pancreatic cancer-associated depression.

Citation Format: Jonathan J. Hue, Hallie J. Graor, Mehrdad Zarei, Ali Vaziri-Gohar, Erryk S. Katayama, Karen Ji, Omid Hajihassani, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. IDO1 is a potential target to combat pancreatic cancer-associated depression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2321.