GADD45β Loss Ablates Innate Immunosuppression in Cancer.

Autor:	Verzella D; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Bennett J; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom., Fischietti M; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Thotakura AK; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom., Recordati C; Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy., Pasqualini F; Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy., Capece D; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Vecchiotti D; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., D'Andrea D; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom., Di Francesco B; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., De Maglie M; Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy., Begalli F; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom., Tornatore L; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom., Papa S; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom.; Current address: Leeds Institute of Cancer and Pathology (LICAP), University of Leeds, Leeds, United Kingdom., Lawrence T; Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France., Forbes SJ; Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom., Sica A; Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.; Department of Pharmaceutical Sciences, Università del Piemonte Orientale 'Amedeo Avogadro', Novara, Italy., Alesse E; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Zazzeroni F; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. g.franzoso@imperial.ac.uk francesca.zazzeroni@univaq.it., Franzoso G; Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London, United Kingdom. g.franzoso@imperial.ac.uk francesca.zazzeroni@univaq.it.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Mar 01; Vol. 78 (5), pp. 1275-1292. Date of Electronic Publication: 2017 Dec 26.
DOI:	10.1158/0008-5472.CAN-17-1833
Abstrakt:	T-cell exclusion from the tumor microenvironment (TME) is a major barrier to overcoming immune escape. Here, we identify a myeloid-intrinsic mechanism governed by the NF-κB effector molecule GADD45β that restricts tumor-associated inflammation and T-cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of proinflammatory tumor-associated macrophages (TAM) and intratumoral immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Furthermore, they suggest a therapeutic target in GADD45β for reprogramming TAM to overcome immunosuppression and T-cell exclusion from the TME. Significance: These findings define a myeloid-based immune checkpoint that restricts T-cell trafficking into tumors, with potentially important therapeutic implications to generally improve the efficacy of cancer immunotherapy. Cancer Res; 78(5); 1275-92. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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