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Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade

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 ex...

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Autores principales: Yang, Rui, Elsaadi, Samah, Misund, Kristine, Abdollahi, Pegah, Vandsemb, Esten Nymoen, Moen, Siv Helen, Kusnierczyk, Anna, Slupphaug, Geir, Standal, Therese, Waage, Anders, Slørdahl, Tobias S, Rø, Torstein Baade, Rustad, Even, Sundan, Anders, Hay, Carl, Cooper, Zachary, Schuller, Alwin G, Woessner, Richard, Borodovsky, Alexandra, Menu, Eline, Børset, Magne, Sponaas, Anne Marit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239696/
https://www.ncbi.nlm.nih.gov/pubmed/32409420
http://dx.doi.org/10.1136/jitc-2020-000610
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author Yang, Rui
Elsaadi, Samah
Misund, Kristine
Abdollahi, Pegah
Vandsemb, Esten Nymoen
Moen, Siv Helen
Kusnierczyk, Anna
Slupphaug, Geir
Standal, Therese
Waage, Anders
Slørdahl, Tobias S
Rø, Torstein Baade
Rustad, Even
Sundan, Anders
Hay, Carl
Cooper, Zachary
Schuller, Alwin G
Woessner, Richard
Borodovsky, Alexandra
Menu, Eline
Børset, Magne
Sponaas, Anne Marit
author_facet Yang, Rui
Elsaadi, Samah
Misund, Kristine
Abdollahi, Pegah
Vandsemb, Esten Nymoen
Moen, Siv Helen
Kusnierczyk, Anna
Slupphaug, Geir
Standal, Therese
Waage, Anders
Slørdahl, Tobias S
Rø, Torstein Baade
Rustad, Even
Sundan, Anders
Hay, Carl
Cooper, Zachary
Schuller, Alwin G
Woessner, Richard
Borodovsky, Alexandra
Menu, Eline
Børset, Magne
Sponaas, Anne Marit
author_sort Yang, Rui
collection PubMed
description 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.
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spelling pubmed-72396962020-05-28 Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade Yang, Rui Elsaadi, Samah Misund, Kristine Abdollahi, Pegah Vandsemb, Esten Nymoen Moen, Siv Helen Kusnierczyk, Anna Slupphaug, Geir Standal, Therese Waage, Anders Slørdahl, Tobias S Rø, Torstein Baade Rustad, Even Sundan, Anders Hay, Carl Cooper, Zachary Schuller, Alwin G Woessner, Richard Borodovsky, Alexandra Menu, Eline Børset, Magne Sponaas, Anne Marit J Immunother Cancer Basic Tumor Immunology 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. BMJ Publishing Group 2020-05-14 /pmc/articles/PMC7239696/ /pubmed/32409420 http://dx.doi.org/10.1136/jitc-2020-000610 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Basic Tumor Immunology
Yang, Rui
Elsaadi, Samah
Misund, Kristine
Abdollahi, Pegah
Vandsemb, Esten Nymoen
Moen, Siv Helen
Kusnierczyk, Anna
Slupphaug, Geir
Standal, Therese
Waage, Anders
Slørdahl, Tobias S
Rø, Torstein Baade
Rustad, Even
Sundan, Anders
Hay, Carl
Cooper, Zachary
Schuller, Alwin G
Woessner, Richard
Borodovsky, Alexandra
Menu, Eline
Børset, Magne
Sponaas, Anne Marit
Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title_full Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title_fullStr Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title_full_unstemmed Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title_short Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade
title_sort conversion of atp to adenosine by cd39 and cd73 in multiple myeloma can be successfully targeted together with adenosine receptor a2a blockade
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239696/
https://www.ncbi.nlm.nih.gov/pubmed/32409420
http://dx.doi.org/10.1136/jitc-2020-000610
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