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Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with
Rui Yang1, Samah Elsaadi1, Kristine Misund1
1Center for Myeloma Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Background:
PD1/PDL1-directed therapies have been unsuccessful for multiple myeloma (MM), an incurable cancer of plasma cells in the bone marrow (BM). Therefore, other immune checkpoints such as extracellular adenosine and its immunosuppressive receptor should be considered. CD39 and CD73 convert extracellular ATP to adenosine, which inhibits T-cell effector functions via the adenosine receptor A2A (A2AR). We set out to investigate whether blocking the adenosine pathway could be a therapy for MM.
Methods:
Expression of CD39 and CD73 on BM cells from patients and T-cell proliferation were determined by flow cytometry and adenosine production by Liquid chromatograpy-mass spectrometry (HPCL/MS). ENTPD1 (CD39) mRNA expression was determined on myeloma cells from patients enrolled in the publicly available CoMMpass study. Transplantable 5T33MM myeloma cells were used to determine the effect of inhibiting CD39, CD73 and A2AR in mice in vivo.
Results:
Elevated level of adenosine was found in BM plasma of MM patients. Myeloma cells from patients expressed CD39, and high gene expression indicated reduced survival. CD73 was found on leukocytes and stromal cells in the BM. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine production and reduced T-cell suppression in vitro in coculture of myeloma and stromal cells. Blocking the adenosine pathway in vivo with a combination of Sodium polyoxotungstate (POM-1), anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased interferon gamma production, and reduced the tumor load in a murine model of MM.
Conclusions:
Our data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.
Insights
Blocking the adenosine pathway shows promise for treating multiple myeloma (MM). Targeting CD39, CD73, and A2AR with inhibitors reduced tumor load and activated immune cells in mice, offering a potential alternative to PD1/PDL1 therapies.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- PD1/PDL1-directed therapies have shown limited success in multiple myeloma (MM).
- The extracellular adenosine pathway, involving CD39 and CD73 enzymes, plays a critical role in immune suppression via the A2A receptor (A2AR).
- Investigating the adenosine pathway as a therapeutic target is crucial for MM treatment.
Purpose of the Study:
- To investigate the potential of blocking the adenosine pathway as a therapeutic strategy for multiple myeloma (MM).
- To evaluate the efficacy of inhibiting CD39, CD73, and A2AR in preclinical models of MM.
Main Methods:
- Flow cytometry and Liquid chromatography-mass spectrometry (LC-MS) were used to analyze CD39 and CD73 expression and adenosine production in MM patient samples.
- In vitro co-culture experiments assessed the impact of CD39 and CD73 inhibition on T-cell suppression.
- In vivo studies utilized a murine model of MM to evaluate the therapeutic effects of combined CD39, CD73, and A2AR inhibition.
Main Results:
- Elevated adenosine levels were detected in the bone marrow (BM) of MM patients.
- Myeloma cells expressed CD39, with high gene expression correlating with reduced survival.
- Inhibition of CD39 and CD73 reduced adenosine production and T-cell suppression in vitro.
- Combined blockade of the adenosine pathway in vivo activated immune cells, enhanced interferon gamma production, and reduced tumor burden in a murine MM model.
Conclusions:
- The adenosine pathway represents a viable therapeutic target for multiple myeloma (MM).
- Blocking this pathway offers a potential alternative to PD1/PDL1 inhibition for MM and other hematological malignancies.
- Available adenosine pathway inhibitors in clinical trials could be rapidly translated to MM patients.
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