Verzella et al. identified GADD45β, an NF-κB-regulated protein, as a marker of poor clinical outcome in many human cancers. They knocked out the Gadd45b gene in the whole mouse, bone marrow (using chimeric mice), or only myeloid cells to demonstrate in several solid cancer models that Gadd45b is a myeloid-intrinsic innate immune checkpoint that reduces proinflammatory tumor-associated macrophage (TAM) activation, restricting tumor-associated inflammation and subsequent T-cell infiltration into the tumor.

T cell exclusion from the tumour microenvironment (TME) is a major barrier to overcoming immune escape. Here we identify a myeloid-intrinsic mechanism governed by the NF-kappaB effector molecule GADD45beta that restricts tumour-associated inflammation and T cell trafficking into tumors. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural 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. Further, they suggest a therapeutic target in GADD45beta for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.

Author Info: (1) DISCAB, University of L'Aquila. (2) CCSI, Department of Medicine, Imperial College London. (3) DISCAB, University of L'Aquila. (4) CCSI, Department of Medicine, Imperial College

Author Info: (1) DISCAB, University of L'Aquila. (2) CCSI, Department of Medicine, Imperial College London. (3) DISCAB, University of L'Aquila. (4) CCSI, Department of Medicine, Imperial College London. (5) Mouse & Animal Pathology Laboratory, Fondazione Filarete. (6) Immunology, Humanitas Clinical and Research Center. (7) DISCAB, University of L'Aquila. (8) DISCAB, University of L'Aquila. (9) CCSI, Department of Medicine, Imperial College London. (10) DISCAB, University of L'Aquila. (11) Mouse & Animal Pathology Laboratory, Fondazione Filarete. (12) CCSI, Department of Medicine, Imperial College London. (13) CCSI, Department of Medicine, Imperial College London. (14) Institute of Cancer and Pathology, University of Leeds. (15) Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Universite de la Mediterranee. (16) University of Edinburgh. (17) Immunity and Inflammation, Fondazione Humanitas per la Ricerca. (18) Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila. (19) Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila. (20) Department of Medicine, CCSI, Imperial College g.franzoso@imperial.ac.uk.

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