Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells.
Sci Rep
; 11(1): 9561, 2021 05 05.
Article
in En
| MEDLINE
| ID: mdl-33953256
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Adenosine
/
Adenosine Monophosphate
/
Alanine
/
Immunologic Memory
Limits:
Humans
Language:
En
Journal:
Sci Rep
Year:
2021
Document type:
Article
Affiliation country:
United States