PGE2 inhibits natural killer and gamma delta T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling.
Natural killer (NK) and unconventional gammadelta 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 gammadelta T cells but it remained uncertain if PGE(2) interferes with the different activating receptors governing the cytolytic responses of NK and gammadelta T cells. In this report, using the model of specific redirected lysis of the mouse FcgammaR(+) cell line P815, we clearly demonstrate that the major NK receptors (NKR): NKG2D, CD16 and natural cytotoxicity receptors (NCR: NKp30, NKp44, NKp46) and gammadelta T cell receptors TCR Vgamma9Vdelta2, NKG2D and CD16 are all inhibited by PGE(2). As is the case with gammadelta 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.
Martinet
Ludovic
L
INSERM, U.563, Centre de Physiopathologie de Toulouse-Purpan, Toulouse F-31300, France. ludovic.martinet@ipbs.fr
Jean
Christine
C
Dietrich
Gilles
G
Fournié
Jean-Jacques
JJ
Poupot
Rémy
R
D000818:Animals; D045744:Cell Line, Tumor; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D015232:Dinoprostone / Q000502:physiology*; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor / Q000276:immunology; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D016692:Receptors, Antigen, T-Cell, gamma-delta; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone