Details

Autor(en) / Beteiligte

• Ray, Arghya
• Song, Yan
• Du, Ting
• Tai, Yu-Tzu
• Chauhan, Dharminder
• Anderson, Kenneth C

Titel

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

Ist Teil von

• Leukemia, 2020-02, Vol.34 (2), p.567-577

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.