Targeting tryptophan catabolic kynurenine pathway enhances antitumor immunity and cytotoxicity in multiple myeloma.

ABSTRACT

Our prior studies showed that dysfunctional plasmacytoid dendritic cells (pDCs) contribute to multiple myeloma (MM) pathogenesis. Specifically, pDC interactions with tumor and T/NK effector cells in the bone marrow (BM) milieu induce immune suppression and MM cell proliferation. Delineation of the mechanism(s) mediating pDC-MM-T-NK cell interactions will identify novel therapeutic targets to both enhance cytotoxicity and anti-MM immunity. Here, we utilized gene expression profiling (GEP) to show that pDC-MM interactions trigger upregulation of immunosuppressive tryptophan catabolic kynurenine (Kyn) pathway. In particular, we show that Kyn pathway enzyme kynurenine-3-monooxygenase (KMO) is upregulated during pDC-MM interactions. Using our coculture models of patient autologous pDC-T-NK-MM cells, we show that pharmacological blockade of KMO activates pDCs and triggers both MM-specific cytotoxic T-cell lymphocytes (CTL) and NK cells cytolytic activity against tumor cells. Furthermore, we show that simultaneous inhibition of Kyn pathway and immune checkpoint PD-L1 enhances antitumor immunity and cytotoxicity in MM. Our preclinical data therefore provide the basis for novel immune-based therapeutic approaches targeting Kyn metabolic pathway enzyme KMO, alone or in combination with anti-PD-L1 Ab, to restore anti-MM immune responses in MM.