Multiple myeloma gammopathies

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

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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.

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Acknowledgements

The grant supports for this investigation were provided by “Dr Miriam and Sheldon Adelson Medical Research Foundation” and by the National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant P50100707, R01CA207237, and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor.

Author information

DC conceptualized the project, designed research, analyzed data, and wrote the paper; AR designed research, performed the experiments, and analyzed the data; YS and TD helped in flow cytometry; Y-TT provided clinical samples, and KCA provided clinical samples, reviewed the data, and wrote the paper.

Correspondence to Dharminder Chauhan or Kenneth C. Anderson.

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Conflict of interest

KCA is on Advisory board of Celgene, Millenium-Takeda, Gilead, Janssen, and Bristol Myers Squibb, and is a Scientific Founder of Oncopep and C4 Therapeutics. DC is a consultant to Stemline Therapeutic, Inc., and equity owner in C4 Therapeutics. The remaining authors declare no conflict of interest.

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Joint Senior authors: Dharminder Chauhan, Kenneth C Anderson

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Ray, A., Song, Y., Du, T. et al. Targeting tryptophan catabolic kynurenine pathway enhances antitumor immunity and cytotoxicity in multiple myeloma. Leukemia (2019) doi:10.1038/s41375-019-0558-x

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