Abstract
Bone marrow plasmacytoid dendritic cells (pDCs) in patients with multiple myeloma (MM) promote tumor growth, survival, drug resistance, and immune suppression. Understanding the molecular signaling crosstalk among the tumor cells, pDCs and immune cells will identify novel therapeutic approaches to enhance anti-MM immunity. Using oligonucleotide arrays, we found that pDC-MM interactions induce metabolic enzyme Alpha-Enolase (ENO1) in both pDCs and MM cells. Analysis of MM patient gene expression profiling database showed that ENO1 expression inversely correlates with overall survival. Protein expression analysis showed that ENO1 is expressed in pDC and MM cells; and importantly, that pDC-MM coculture further increases ENO1 expression in both MM cells and pDCs. Using our coculture models of patient autologous pDC-T-NK-MM cells, we examined whether targeting ENO1 can enhance anti-MM immunity. Biochemical inhibition of ENO1 with ENO1 inhibitor (ENO1i) activates pDCs, as well as increases pDC-induced MM-specific CD8+ CTL and NK cell activity against autologous tumor cells. Combination of ENO1i and anti-PD-L1 Ab or HDAC6i ACY-241 enhances autologous MM-specific CD8+ CTL activity. Our preclinical data therefore provide the basis for novel immune-based therapeutic approaches targeting ENO1, alone or in combination with anti-PD-L1 Ab or ACY241, to restore anti-MM immunity, enhance MM cytotoxicity, and improve patient outcome.
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Change history
07 September 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41388-021-01996-y
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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.
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D.C. conceptualized the project, designed research, analyzed data, and wrote the paper; A.R. designed research, performed the experiments, and analyzed the data; Y.S. and T.D. helped in flow cytometry; and K.C.A. provided clinical samples, and reviewed the manuscript.
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K.C.A. is on Advisory board of Celgene, Millenium-Takeda, Gilead, Janssen, and Bristol Myers Squibb, and is a Scientific Founder with financial interest in Acetylon, Oncopep and C4 Therapeutics. D.C. is consultant to Stemline Therapeutic, Inc., Oncopeptides AB; and Equity owner in C4 Therapeutics. The remaining authors declare no conflict of interest.
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Ray, A., Song, Y., Du, T. et al. Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma. Oncogene 39, 2786–2796 (2020). https://doi.org/10.1038/s41388-020-1172-0
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DOI: https://doi.org/10.1038/s41388-020-1172-0
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