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

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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 A2A receptors (A2ARs) 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/A2AR 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 A2AR agonists (such as CADO or CGS21680) increases their cytotoxic activity and induces resistance to EP2R and A2AR inhibitory signaling (cross-resistance) due to homologous and heterologous desensitization and internalization of EP2Rs and A2ARs, 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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Acknowledgments

We thank Dr. Steven Rosenberg and Dr. John Wonderlich for generously providing samples of TILs for these studies. This work was supported by the DOD, Award BC051720, and Hillman Foundation (E.G.), NIH grants DK68575 and DK79307 (EKJ).

Conflict of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA, 15213, USA

    Yunyun Su & Elieser Gorelik

  2. Department of Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Ave, Pittsburgh, PA, 15213, USA

    Elieser Gorelik

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA

    Edwin K. Jackson

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  1. Yunyun Su
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Correspondence to Elieser Gorelik.

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Su, Y., Jackson, E.K. & Gorelik, E. Receptor desensitization and blockade of the suppressive effects of prostaglandin E2 and adenosine on the cytotoxic activity of human melanoma-infiltrating T lymphocytes. Cancer Immunol Immunother 60, 111–122 (2011). https://doi.org/10.1007/s00262-010-0924-z

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