title: Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection.
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.
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Sektioglu
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Noemi
authors.initials: N
authors.lastname: Bender
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Institutes of Molecular Medicine and Experimental Immunology, University of Bonn , Bonn, Germany.
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.affiliation: 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.
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: Immune Monitoring Unit, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.affiliation: Immune Monitoring Unit, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Urban
authors.affiliation: Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Applied Tumor Biology Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel-Döberitz
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, NIH , Frederick, MD, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Somasundaram
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, NIH , Frederick, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wink
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany; Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Regensburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
keywords: Adoptive T-cell transfer; NO; T-cell infiltration; endothelial adhesion molecules; endothelial barrier; iNOS+ macrophage; tumor therapy