Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells

Abstract Extracellular adenosine suppresses T cell immunity in the tumor microenvironment and in vitro treatment of memory T cells with adenosine can suppress antigen-mediated memory T cell expansion. We describe utilizing the recall antigen assay platform to screen small molecule drug off-target ef...

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Autores principales: Eden Kleiman, Gloria Sierra, Binchen Mao, Dennie Magcase, Marybeth V. George, Pirouz M. Daftarian
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/cca0be82758d4e3d8e345de69c239545
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spelling oai:doaj.org-article:cca0be82758d4e3d8e345de69c2395452021-12-02T15:37:58ZAdenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells10.1038/s41598-021-88965-32045-2322https://doaj.org/article/cca0be82758d4e3d8e345de69c2395452021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88965-3https://doaj.org/toc/2045-2322Abstract Extracellular adenosine suppresses T cell immunity in the tumor microenvironment and in vitro treatment of memory T cells with adenosine can suppress antigen-mediated memory T cell expansion. We describe utilizing the recall antigen assay platform to screen small molecule drug off-target effects on memory T cell expansion/function using a dosing regimen based on adenosine treatment. As a proof of principle, we show low dose GS-5734, a monophosphoramidate prodrug of an adenosine analog, does not alter memory T cell recall at lower doses whereas toxicity observed at high dose favors antigen-specific memory T cell survival/proliferation over non-specific CD8+ T cells. Conversely, parent nucleoside GS-441524 at high dosage does not result in cellular toxicity and reduces antigen-specific T cell recall in most donors. Despite similar chemical structure, these drugs displayed opposing effects on memory T cell expansion and viability highlighting the sensitivity of this assay setup in screening compounds for off-target effects.Eden KleimanGloria SierraBinchen MaoDennie MagcaseMarybeth V. GeorgePirouz M. DaftarianNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Eden Kleiman
Gloria Sierra
Binchen Mao
Dennie Magcase
Marybeth V. George
Pirouz M. Daftarian
Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
description Abstract Extracellular adenosine suppresses T cell immunity in the tumor microenvironment and in vitro treatment of memory T cells with adenosine can suppress antigen-mediated memory T cell expansion. We describe utilizing the recall antigen assay platform to screen small molecule drug off-target effects on memory T cell expansion/function using a dosing regimen based on adenosine treatment. As a proof of principle, we show low dose GS-5734, a monophosphoramidate prodrug of an adenosine analog, does not alter memory T cell recall at lower doses whereas toxicity observed at high dose favors antigen-specific memory T cell survival/proliferation over non-specific CD8+ T cells. Conversely, parent nucleoside GS-441524 at high dosage does not result in cellular toxicity and reduces antigen-specific T cell recall in most donors. Despite similar chemical structure, these drugs displayed opposing effects on memory T cell expansion and viability highlighting the sensitivity of this assay setup in screening compounds for off-target effects.
format article
author Eden Kleiman
Gloria Sierra
Binchen Mao
Dennie Magcase
Marybeth V. George
Pirouz M. Daftarian
author_facet Eden Kleiman
Gloria Sierra
Binchen Mao
Dennie Magcase
Marybeth V. George
Pirouz M. Daftarian
author_sort Eden Kleiman
title Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
title_short Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
title_full Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
title_fullStr Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
title_full_unstemmed Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells
title_sort adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory t cells
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/cca0be82758d4e3d8e345de69c239545
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