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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
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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Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells

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