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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2021
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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) |
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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 |
work_keys_str_mv |
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