%0 Journal Article
%A Sektioglu, Ibrahim M
%A Carretero, Rafael
%A Bender, Noemi
%A Bogdan, Christian
%A Garbi, Natalio
%A Umansky, Viktor
%A Umansky, Ludmila
%A Urban, Katharina
%A Knebel Döberitz, Christina
%A Somasundaram, Veena
%A Wink, David
%A Beckhove, Philipp
%A Hämmerling, Günter
%T Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection.
%J OncoImmunology
%V 5
%N 10
%@ 2162-402X
%C Austin, Tex.
%I Landes Bioscience
%M DKFZ-2017-05620
%P e1204506 -
%D 2016
%X In tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing tumor macrophages in T-cell infiltration and tumor rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS(+) macrophages in tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These results will be valuable for the development of strategies designed to overcome the paucity of T-cell infiltration into tumors that is a major obstacle in clinical cancer immunotherapy.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:27853636
%2 pmc:PMC5087300
%R 10.1080/2162402X.2016.1204506
%U https://inrepo02.dkfz.de/record/130541