Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection Sektioglu, Ibrahim M. Carretero Coca, Rafael Hämmerling, Günter J. Cancer Immunology Macrophage Nitric oxide G.J.H. was supported by the Wilhelm Sander-Stiftung, N.G. by the Deutsche Forschungsgemeinschaft (SFB 704, and C.B. by the Deutsche Forschungsgemeinschaft (SFB 643 and SFB 1181) and the Interdisciplinary Center for Clinical Research of the University Hospital Erlangen (project A61). Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany. Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany. Institutes of Molecular Medicine and Experimental Immunology, University of Bonn , Bonn, Germany. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. Immune Monitoring Unit, German Cancer Research Center (DKFZ) , Heidelberg, Germany. Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Applied Tumor Biology Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Cancer and Inflammation Program, National Cancer Institute, NIH , Frederick, MD, USA. Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany; Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Regensburg, Germany. 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. 2025-10-31T12:30:56Z 2025-10-31T12:30:56Z 2016-08-09 journal article Sektioglu, Ibrahim M. et al. Oncoimmunology. 2016 Aug 9;5(10):e1204506. eCollection 2016. doi: 10.1080/2162402X.2016.1204506 https://hdl.handle.net/10481/107657 10.1080/2162402X.2016.1204506 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Taylor & Francis