JSR Life Sciences, 1280 North Mathilda Avenue, Sunnyvale, CA, 94089, USA.
Crown Bioscience Inc., 16550 W Bernardo Dr Building 5, Suite 525, San Diego, CA, 92127, USA.
Sci Rep. 2021 May 5;11(1):9561. doi: 10.1038/s41598-021-88965-3.
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.
细胞外腺苷在肿瘤微环境中抑制 T 细胞免疫，体外用腺苷处理记忆 T 细胞可以抑制抗原介导的记忆 T 细胞扩增。我们描述了利用回忆抗原检测平台，根据腺苷处理的剂量方案，筛选小分子药物对记忆 T 细胞扩增/功能的脱靶效应。作为原理验证，我们展示了低剂量的 GS-5734，一种腺苷类似物的单磷酰胺前药，在较低剂量下不会改变记忆 T 细胞的回忆，而在高剂量下观察到的毒性有利于抗原特异性记忆 T 细胞的存活/增殖而不是非特异性 CD8 T 细胞。相反，核苷母体 GS-441524 在高剂量下不会导致细胞毒性，并降低大多数供体的抗原特异性 T 细胞回忆。尽管具有相似的化学结构，但这些药物对记忆 T 细胞的扩增和活力显示出相反的作用，突出了该检测系统在筛选化合物的脱靶效应方面的敏感性。
