Tryptophan metabolism and the plasma cell/multiple myeloma microenvironment 3907

Description Normal Long-Lived Plasma Cells (LLPC) and their malignant counterparts Multiple Myeloma (MM) depend on the Bone marrow Microenvironment (BMME) for survival. We have previously shown that LLPCs and MM interact with BMME Dendritic Cells (DC) which induces DC production of Indolamine Dioxygenase 1 (IDO1), which catabolizes tryptophan (TRP) to kynurenine (KYN). Depletion of TRP suppresses T effector cell activation and the production of KYN activates pro-survival pathways in LLPC and MM through the activation of the transcription factor Aryl Hydrocarbon Receptor (AHR). We now show that MM cells can produce KYN independent of DCs through expression of the TRP catabolizing enzyme Tryptophan Dioxygenase (TDO), indicating a mechanism by which MM can become independent of the BMME. Inhibiting or knocking down TDO significantly reduced MM cell survival. Inhibiting TDO reduced KYN production and AHR activation in TDO+ MM cell lines, but did not affect a TDO- MM cell line. Co-culture with IDO1+ DCs or treatment with AHR ligand TCDD rescued MM cell viability from TDO inhibitor-induced cell death, indicating that TRP metabolism to KYN is important to MM survival. TRP metabolism in a novel treatment target in MM and could lead to more effective cell killing and immunotherapy. LLPC and MM depend on different methods of TRP metabolism for survival both in the BMME and as they become independent of it.