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Br J Pharmacol. 2009 Jan;156(2):297-306. doi: 10.1111/j.1476-5381.2008.00019.x. Epub 2008 Dec 9.

In vitro induction of T cells that are resistant to A2 adenosine receptor-mediated immunosuppression.

Author information

1
New England Inflammation and Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. a.ohta@neu.edu

Abstract

BACKGROUND AND PURPOSE:

The increased levels of extracellular adenosine in inflamed tissues down-regulate activated immune cells via the A(2A) adenosine receptor. This A(2A) adenosine receptor-mediated immunosuppression is a disqualifying obstacle in cancer immunotherapy as it protects cancerous tissues from adoptively transferred anti-tumour T cells. The aim of this study was to test whether the negative selection of T cells will produce T cells that are resistant to inhibition by extracellular adenosine.

EXPERIMENTAL APPROACH:

Cytotoxic T lymphocytes (CTL) were developed by mixed lymphocyte culture in the presence or absence of the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). The sensitivity of CTL to adenosine analogues was characterized by cAMP induction, interferon-gamma production and cytotoxicity.

KEY RESULTS:

CTL that could proliferate even in the presence of NECA were less susceptible to inhibition by A(2A) adenosine receptor agonists, as shown by a much smaller accumulation of cAMP and less inhibition of interferon-gamma production compared with control CTL. The successful protocol to produce CTL that are both resistant to adenosine-mediated immunosuppression and maintain strong cytotoxicity and interferon-gamma secretion required NECA to be added only during the expansion stage after the establishment of CTL. In contrast, the priming of resting T cells in the presence of NECA resulted in T cells with impaired effector functions.

CONCLUSIONS AND IMPLICATIONS:

Adenosine-resistant effector T cells were successfully obtained by exposure of activated T cells to NECA. These in vitro studies form the basis for future attempts to produce anti-tumour T cells that are more effective in adoptive immunotherapy.

PMID:
19076726
PMCID:
PMC2697837
DOI:
10.1111/j.1476-5381.2008.00019.x
[Indexed for MEDLINE]
Free PMC Article

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