Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection
| Autor: | Rafael Carretero, Viktor Umansky, Günter J. Hämmerling, Magnus von Knebel-Döberitz, Ibrahim M. Sektioglu, Christian Bogdan, Katharina Urban, David A. Wink, Natalio Garbi, Ludmila Umansky, Veena Somasundaram, Philipp Beckhove, Noemi Bender |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell adhesion molecule T cell Lymphocyte medicine.medical_treatment Immunology Biology medicine.disease Extravasation Cell biology Nitric oxide Endothelial activation 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology medicine.anatomical_structure Oncology chemistry Cancer immunotherapy medicine Immunology and Allergy Infiltration (medical) Original Research |
| Zdroj: | Oncoimmunology. 5(10) |
| ISSN: | 2162-4011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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