The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.

TitleThe interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.
Publication TypeJournal Article
Year of Publication2023
AuthorsStagg J, Golden E, Wennerberg E, Demaria S
JournalSci Immunol
Date Published2023 Jul 14
KeywordsAdenosine, Adenosine Monophosphate, Adenosine Triphosphate, DNA Damage, Humans, Neoplasms, Tumor Microenvironment

The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.

Alternate JournalSci Immunol
PubMed ID37418547
PubMed Central IDPMC10394739
Grant ListR01 CA201246 / CA / NCI NIH HHS / United States
Related Faculty: 
Sandra Demaria, M.D.

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