Targeting Overexpressed IDO in Stromal Cells as a Potential Therapeutic Strategy in Multiple Myeloma

ABSTRACT Stromal cells are an essential component of the tumor microenvironment (TME) in multiple myeloma (MM). Indoleamine 2,3‐dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), plays an immunosuppressive role in the TME. We previously reported that a high Kyn/Trp ratio was associated with poor prognosis in lenalidomide‐treated refractory/relapsed MM patients and that IDO expression in stromal cells was upregulated by co‐culture with MM cells. Here, we analyzed the mechanism through which MM cells upregulate IDO in stromal cells and aimed to identify compounds that inhibit IDO upregulation. Two MM cell lines, XG‐7 and IM‐9, upregulated IDO in stromal cells both directly and indirectly. These two MM cell lines also upregulated programmed cell death ligand 1 (PD‐L1) in stromal cells, which was closely related to IDO upregulation. RNA sequencing analysis revealed that cytokine signaling pathways were commonly upregulated in stromal cells co‐cultured with these two MM cell lines. In stromal cells co‐cultured with MM cells, signal transducer and activator of transcription 1 (STAT1) and nuclear factor‐κB (NF‐κB) p65 was phosphorylated, and interferon regulatory factor 1 (IRF1), which binds to the IDO promoter region, was strongly upregulated. This IDO and IRF1 upregulation were abolished by Janus kinase (JAK) inhibitor. In addition, stromal cells with knockout of IRF1 showed little upregulation of IDO when co‐cultured with MM cells. These results suggest that the JAK–STAT1–NF‐κB–IRF1 signaling pathway may be involved in IDO upregulation. JAK inhibitors may improve the TME in MM and positively influence immunotherapy outcomes.