IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

SIMPLE SUMMARY: The tryptophan-catabolizing enzyme IDO1 and its metabolite kynurenine were shown to be enhanced in patients with chronic lymphocytic leukemia (CLL), and their involvement in T cell suppression and immune escape was suggested. As we have observed increased IDO1 expression and kynurenine serum levels in the Eµ-TCL1 mouse model of CLL, we evaluated the therapeutic potential of targeting IDO1 in preclinical treatment studies with two IDO1 inhibitors in mice developing CLL. As both studies revealed only minor effects of IDO1 inhibition on leukemia development and the immune compartment at early time points of treatment which disappeared over time, our data suggest that even though IDO1 might be involved in immunosuppressive mechanisms in CLL, its targeting is not sufficient for preventing immune escape. Thus, compensatory mechanisms beyond IDO1 seem to be of relevance to prevent clinically relevant benefits with IDO1-targeting drugs. ABSTRACT: Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.