Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma
Arghya Ray1, Yan Song1, Ting Du1
1Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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.
Insights
Targeting Alpha-Enolase (ENO1) in multiple myeloma (MM) reactivates immune cells. Inhibiting ENO1 enhances anti-MM immunity and tumor cell killing, offering new therapeutic strategies.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Plasmacytoid dendritic cells (pDCs) in multiple myeloma (MM) patients foster tumor progression and immune evasion.
- Understanding molecular interactions between tumor cells and pDCs is crucial for developing novel anti-MM therapies.
Purpose of the Study:
- To investigate the role of Alpha-Enolase (ENO1) in pDC-MM interactions and evaluate ENO1 inhibition as a therapeutic strategy.
- To identify molecular signaling pathways involved in immune suppression within the MM microenvironment.
Main Methods:
- Oligonucleotide arrays and gene expression profiling to analyze ENO1 induction in pDC-MM interactions.
- Coculture models using patient-derived autologous pDC-T-NK-MM cells.
- Biochemical inhibition of ENO1 using a specific inhibitor (ENO1i) and combination therapies.
Main Results:
- pDC-MM interactions induce ENO1 expression in both cell types, correlating inversely with patient survival.
- ENO1 inhibition (ENO1i) activates pDCs and enhances CD8+ CTL and NK cell activity against MM cells.
- Combination therapy with ENO1i and anti-PD-L1 antibody or ACY241 further boosts MM-specific CD8+ CTL responses.
Conclusions:
- ENO1 is a key mediator in the pDC-MM crosstalk, promoting immune suppression.
- Targeting ENO1, alone or in combination with other agents, can restore anti-MM immunity and enhance anti-tumor cytotoxicity.
- Preclinical data support ENO1-targeting therapies for improving outcomes in multiple myeloma patients.
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