PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

Natural killer (NK) and unconventional gamma delta T cells, by their ability to sense ligands induced by oncogenic stress on cell surface and to kill tumor cells without a need for clonal expansion, show a great therapeutic interest They use numerous activating and inhibitory receptors which can function with some independence to trigger or inhibit destruction of target cells Previous reports demonstrated that PGE(2) is able to suppress the destruction of some tumor cell lines by NK and gamma delta T cells but it remained uncertain if PGE(2) interferes with the different activating receptors governing the cytolytic responses of NK and gamma delta T cells In this report, using the model of specific redirected lysis of the mouse Fc gamma R' cell line P815, we clearly demonstrate that the major NK receptors (NKR) NKG2D, CD16 and natural cytotoxiaty receptors (NCR: NKp30, NKp44, NKp46) and gamma delta T cell receptors TCR V gamma 9V delta 2, NKG2D and CD16 are all inhibited by PGE(2) As is the case with gamma delta T cells, we show that PGE(2) binds on E-prostanoid 2 (EP2) and EP4 receptors on NK cells Finally, we delineate that the signaling of the blockade by PGE(2) is mediated through a cAMP-dependent activation of PKA type I which inhibits early signaling protein of cytotoxic cells In the discussion, we focused on how these data should impact particular approaches in the treatment of cancer. (C) 2010 Elsevier Inc. All rights reserved.