IDO-1 inhibitor INCB24360 elicits distant metastasis of basal extruded cancer cells in pancreatic ductal adenocarcinoma

Hada Buhe1,2, Ji-xin Ma1, Fang-zhou Ye1, Chen-yun Song1, Xin-yu Chen1, Yang Liu1, Huang Lin3, Xu Han4, Li-xiang Ma1, Hexige Saiyin3
1 Department of Anatomy, Histology & Embryology, School of Basic Medical Science, Fudan University, Shanghai 200032, China
2 The School of Pharmacy, Fujian Medical University, Fuzhou 350108, China
3 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China
4 Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Correspondence to: Li-xiang Ma:, Hexige Saiyin:,
DOI: 10.1038/s41401-022-01035-w
Received: 21 July 2022
Accepted: 20 November 2022
Advance online: 14 December 2022


Neoplastic cells of non-immunogenic pancreatic ductal adenocarcinoma (PDAC) express indoleamine 2,3-dioxygenase 1 (IDO-1), an immunosuppressive enzyme. The metabolites of IDO-1 in cancers provide one-carbon units that annihilate effector T cells, and recruit immunosuppressive cells. In this study we investigated how IDO-1 affected the neoplastic cell behaviors in PDACs. Using multiple markers co-labeling method in 45-μm-thick tissue sections, we showed that IDO-1 expression was uniquely increased in the neoplastic cells extruded from ducts’ apical or basal domain, but decreased in lymph metastatic cells. IDO-1+ extruding neoplastic cells displayed increased vimentin expression and decreased cytokeratin expression in PDACs, characteristics of epithelial-mesenchymal transition (EMT). However, IDO-1 expression was uncorrelated with immunosuppressive infiltrates and clinicopathological characteristics of grim outcome. We replicated basal extrusion with EMT in murine KPIC PDAC organoids by long-term IFN-γ induction; application of IDO-1 inhibitor INCB24360 or 1-MT partially reversed basal extrusion coupled EMT. Ido-1 deletion in KPIC cells deprived its tumorigenicity in immunocompetent mice, decreased cellular proliferation and macropinocytic ability, and increased immunogenicity. KPIC organoids with IFN-γ-induced basal extrusion did not accelerate distant metastasis, whereas inhibition IFN-γ-induced IDO-1 with INB24360 but not 1-MT in KPIC organoids elicited liver metastasis of subcutaneous KPIC organoid tumors, suggesting that lower IDO-1 activity accelerated distant metastasis, whereas IDO-1 was indispensable for tumorigenicity of PDAC cells and supports the survival of extruding cells.
Keywords: pancreatic ductal adenocarcinoma; basal extrusion; IDO-1; INCB24360; liver metastasis; murine KPIC PDAC organoids

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