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

Author:

Sektioglu, I. M.

Carretero, R.

Bender, N.

Bogdan, C.

Garbi, N.

Umansky, V.

Umansky, L.

Urban, K.

von Knebel-Doberitz, M.

Somasundaram, V.

Wink, D.

Beckhove, P.

Hammerling, G. J.
Author Address

Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.;Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universitat (FAU) Erlangen-Nurnberg, Universitatsklinikum 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.

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.

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