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Oncoimmunology. 2016 Aug 9;5(10):e1204506. eCollection 2016.

Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection.

Author information

1
Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
2
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen , Erlangen, Germany.
3
Institutes of Molecular Medicine and Experimental Immunology, University of Bonn , Bonn, Germany.
4
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.
5
Immune Monitoring Unit, German Cancer Research Center (DKFZ) , Heidelberg, Germany.
6
Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Applied Tumor Biology Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
7
Cancer and Inflammation Program, National Cancer Institute, NIH , Frederick, MD, USA.
8
Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany; Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Regensburg, Germany.

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.

KEYWORDS:

Adoptive T-cell transfer; NO; T-cell infiltration; endothelial adhesion molecules; endothelial barrier; iNOS+ macrophage; tumor therapy

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