Expression of IDO1 is regulated via Ras signaling pathways.

Ras proteins are among the most widely studied proto-oncogene products. Ras proteins are membrane-anchored GTPases that participate in multiple signaling cascades regulating crucial cellular processes including cell survival, proliferation, and differentiation. Ras mutations and/or deregulated Ras activities frequently lead to inflammation and malignant transformation. Recent studies have also shown that Ras mutations are associated with immuno-resistance by positive regulation of PD-L1 expression. Indoleamine 2,3-dioxygenases 1 (IDO1) is a heme-containing enzyme that catalyzes the rate limiting step of conversion of tryptophan into kynurenine (Kyn). Extensive research in the past has shown that IDO1 and its catalytic product Kyn mediate immune tolerance, thus promoting tumorigenesis in vivo. IDO1 expression is activated by immune cytokines including interferon-γ (IFN-γ)and interleukin-6 (IL-6). However, whether there is a mechanistic link between oncogenic KRas and IDO1 expression and how IDO1 expression contributes to immune invasion of transformed cells with KRas mutations remain unclear. Here we report that oncogenic KRas significantly enhanced IFN-γ-induced IDO1 expression. In H358 lung carcinoma cells, IDO1 expression induced by IFN-γ was at least in part dependent on ERK activation, and treatment with ARS-1620, a covalent KRas inhibitor, suppressed IDO1 expression induced by IFN-γαμμα in a concentration-dependent manner. IDO1 expression was also induced by IFN-γ in HCT116 colon carcinoma cells that harbored a KRas mutant allele, but not in HCT116 cells with wild-type KRas, suggesting that IFN-γ induced IDO1 expression requires Ras activation. In addition, KRas downregulation by specific siRNAs decreased IFN-γ-induced IDO1 expression in A549 lung cancer cells. Taken together, our study strongly suggests that Ras/ERK signaling pathway plays an important role in promoting IDO1 expression induced by IFN-γ.