Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection. (2nd October 2016)

• Record Type: Journal Article
• Authors: Sektioglu, Ibrahim M.; Carretero, Rafael; Bender, Noemi; Bogdan, Christian; Garbi, Natalio; Umansky, Viktor; Umansky, Ludmila; Urban, Katharina; von Knebel-Döberitz, Magnus; Somasundaram, Veena; Wink, David; Beckhove, Philipp; Hämmerling, Günter J.
• Is Part Of: Oncoimmunology. Volume 5:Number 10(2016)
• Publication Date: 2016-10-02
• Subjects: Adoptive T-cell transfer -- endothelial adhesion molecules -- endothelial barrier -- iNOS+ macrophage -- NO -- tumor therapy -- T-cell infiltration; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1204506
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: 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.