Pharmacological targeting of immune checkpoint A2aR improves function of anti-CD19 CAR T cells in vitro

•Adenosine-enriched tumor microenvironment limits the efficacy of CAR T cell therapy.•CAR-mediated activation augments A2aR expression in the huCAR19 T cells in vitro.•Pharmacological targeting of A2aR boosts proliferation and cytokine production of huCAR19 T cells in vitro. In spite of impressive r...

Full description

Saved in:
Bibliographic Details
Published in:Immunology letters 2020-07, Vol.223, p.44-52
Main Authors: Fallah-Mehrjardi, Keyvan, Mirzaei, Hamid Reza, Masoumi, Elham, Jafarzadeh, Leila, Rostamian, Hosein, Khakpoor-Koosheh, Mohammad, Alishah, Khadijeh, Noorbakhsh, Farshid, Hadjati, Jamshid
Format: Article
Language:English
Subjects:
A2aR
Adenosine
Chimeric antigen receptor T cells
Tumor microenvironment
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•Adenosine-enriched tumor microenvironment limits the efficacy of CAR T cell therapy.•CAR-mediated activation augments A2aR expression in the huCAR19 T cells in vitro.•Pharmacological targeting of A2aR boosts proliferation and cytokine production of huCAR19 T cells in vitro. In spite of impressive results in the treatment of acute lymphoblastic B cell leukemia (B-ALL) with chimeric antigen receptor (CAR) T cells, the clinical outcome of some hematological cancers like follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) has not been very promising likely due to immunosuppressive networks within tumor microenvironment. Hypoxia in the microenvironment of hematological malignancies and consequently generation of adenosine molecule is appeared to be correlated with immunosuppression, tumor progression, and relapse. Herein, we hypothesized that whether pharmacological targeting of adenosine 2a receptor (A2aR) can enhance antitumor activity of anti-CD19 CAR T cells in vitro. Prior to functional assays, A2aR expression was assessed in CAR-expressing T cells. Our results showed that A2aR was not only up-regulated in the fully human anti-CD19 CAR T cells (hereafter referred to as huCAR19 T cells) but also was further overexpressed following re-stimulation with target cells. Although pharmacological inhibition of A2aR could significantly increase proliferation capacity and cytokine production of huCAR19 T cells following treatment with an adenosine analog, cytotoxic activity of huCAR19 T cells was not significantly improved. Considering A2aR overexpression in huCAR19 T cells in the tumor microenvironment, our results indicated that pharmacological targeting of A2aR could not only improve huCAR19 T cells functionality in a hostile tumor microenvironment but also could have a therapeutic advantage, and sought to assess the possibility in a pre-clinical setting.
ISSN:0165-2478
1879-0542
DOI:10.1016/j.imlet.2020.04.005