1. GADD45β loss ablates innate immunosuppression in cancer
- Author
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Francesca Zazzeroni, Fabio Pasqualini, Stuart J. Forbes, Federica Begalli, Jason Bennett, Mariafausta Fischietti, Laura Tornatore, Daniel D'Andrea, Toby Lawrence, Barbara Di Francesco, Antonio Sica, Anil K. Thotakura, Marcella De Maglie, Daria Capece, Salvatore Papa, Camilla Recordati, Guido Franzoso, Daniela Verzella, Edoardo Alesse, Davide Vecchiotti, Medical Research Council (MRC), Cancer Research UK, Bloodwise, Department of Immunology and Cell Biology, Mario Negri Institute, Department of Physics [Roma La Sapienza], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Department of Biotechnological and Applied Clinical Sciences, Università degli Studi dell'Aquila (UNIVAQ), Dipartimento di Fisica [Roma La Sapienza], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi dell'Aquila = University of L'Aquila (UNIVAQ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
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0301 basic medicine ,Male ,Cancer Research ,Myeloid ,GADD45β, NF-κB, Inflammation, Tumor associated macrophage (TAM), Tumour microenvironment (TME) ,medicine.medical_treatment ,T-Lymphocytes ,NF-KAPPA-B ,DIVERSITY ,PROGRESSION ,Apoptosis ,Tumor associated macrophage (TAM) ,medicine.disease_cause ,NF-κB ,Immune tolerance ,Mice ,Cancer immunotherapy ,Tumour microenvironment (TME) ,HEPATOCELLULAR-CARCINOMA ,Neoplasms ,Tumor Cells, Cultured ,Tumor Microenvironment ,Medicine ,Myeloid Cells ,Mice, Knockout ,Liver Neoplasms ,Immunosuppression ,3. Good health ,TUMOR-ASSOCIATED MACROPHAGES ,medicine.anatomical_structure ,Oncology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,GADD45β ,Life Sciences & Biomedicine ,Carcinoma, Hepatocellular ,Article ,03 medical and health sciences ,INFILTRATING MACROPHAGES ,LYMPHOID STRUCTURES ,INFLAMMATION ,Journal Article ,Biomarkers, Tumor ,Immune Tolerance ,Animals ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,IMMUNOTHERAPY ,Cell Proliferation ,Immunosuppression Therapy ,Tumor microenvironment ,Science & Technology ,business.industry ,Macrophages ,Cancer ,medicine.disease ,Antigens, Differentiation ,Immune checkpoint ,Mice, Inbred C57BL ,030104 developmental biology ,CELLS ,Cancer research ,business ,Carcinogenesis - Abstract
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.
- Published
- 2017
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