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01-01-2011 | Original Article

Receptor desensitization and blockade of the suppressive effects of prostaglandin E₂ and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes

Authors: Yunyun Su, Edwin K. Jackson, Elieser Gorelik

Published in: Cancer Immunology, Immunotherapy | Issue 1/2011

Abstract

Previous studies document that PGE₂ and adenosine suppress production of inflammatory cytokines. The present study demonstrates for the first time that (1) PGE₂ and 2-chloroadenosine (CADO; a stable analog of adenosine) directly inhibit the cytolytic function of human tumor-infiltrating lymphocytes (TILs); (2) the combination PGE₂ and CADO have additive suppressive effects; and (3) the cooperative immunosuppressive actions of PGE₂ and CADO are mediated via EP2 receptors (EP2Rs) and A_2A receptors (A_2ARs) and are due to amplification of cAMP production, activation of protein kinase A (PKA) and T cell receptor (TCR) inhibitor Csk leading to inhibition of Lck, ZAP-70 and Akt phosphorylation. (4) During ex vivo expansion, TILs undergo three stages of differentiation converting from TILs with high cytotoxic activity and relative resistance to combined EP2R/A_2AR suppression (stage I) to TILs retaining high cytotoxicity and gaining sensitivity to combined suppression (stage II) and then to TILS that are less cytotoxic and very sensitive to combined suppression (stage III). (5) Finally, we find that pretreatment of TILs with non-inhibitory concentrations of EP2R agonists (such as PGE₂ or butaprost) or A_2AR agonists (such as CADO or CGS21680) increases their cytotoxic activity and induces resistance to EP2R and A_2AR inhibitory signaling (cross-resistance) due to homologous and heterologous desensitization and internalization of EP2Rs and A_2ARs, thus preventing their inhibitory signaling. We conclude that inducing resistance of TILs to the suppressive effects of PGE₂ and adenosine in the tumor microenvironment could represent a novel strategy for improving the efficacy of adoptive immunotherapy.

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Title: Receptor desensitization and blockade of the suppressive effects of prostaglandin E2 and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes
Authors: Yunyun Su
Edwin K. Jackson
Elieser Gorelik
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 1/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-010-0924-z

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