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GADD45β loss ablates innate immunosuppression in cancer

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Verzella et al Cancer Research 2017 - Manuscript.pdfAccepted version12.41 MBAdobe PDFView/Open
Verzella et al - Supplementary information .pdfSupporting information212.25 kBAdobe PDFView/Open
Verzella et al - Supplementary Figures.pdfSupporting information19.22 MBAdobe PDFView/Open
Title: GADD45β loss ablates innate immunosuppression in cancer
Authors: Verzella, D
Bennett, J
Fischietti, M
Thotakura, AK
Recordati, C
Pasqualini, F
Capece, D
Vecchiotti, D
D'Andrea, D
Di Francesco, B
De Maglie, M
Begalli, F
Tornatore, L
Papa, S
Lawrence, T
Forbes, SJ
Sica, A
Alesse, E
Zazzeroni, F
Franzoso, G
Item Type: Journal Article
Abstract: 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-κB effector molecule GADD45β that restricts tumour-associated inflammation and T cell trafficking into tumours. 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 GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.
Issue Date: 1-Mar-2018
Date of Acceptance: 19-Dec-2017
URI: http://hdl.handle.net/10044/1/55461
DOI: 10.1158/0008-5472.CAN-17-1833
ISSN: 1538-7445
Publisher: American Association for Cancer Research
Start Page: 1275
End Page: 1292
Journal / Book Title: Cancer Research
Volume: 78
Issue: 5
Copyright Statement: ©2017 American Association for Cancer Research.
Sponsor/Funder: Medical Research Council (MRC)
Cancer Research UK
Bloodwise
Funder's Grant Number: MR/L005069/1
15115
15003
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
NF-KAPPA-B
TUMOR-ASSOCIATED MACROPHAGES
INFILTRATING MACROPHAGES
HEPATOCELLULAR-CARCINOMA
LYMPHOID STRUCTURES
PROGRESSION
CELLS
IMMUNOTHERAPY
INFLAMMATION
DIVERSITY
Animals
Antigens, Differentiation
Apoptosis
Biomarkers, Tumor
Carcinoma, Hepatocellular
Cell Proliferation
Female
Humans
Immune Tolerance
Immunosuppression
Liver Neoplasms
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells
Neoplasms
T-Lymphocytes
Tumor Cells, Cultured
Tumor Microenvironment
T-Lymphocytes
Tumor Cells, Cultured
Macrophages
Myeloid Cells
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Mice
Neoplasms
Carcinoma, Hepatocellular
Liver Neoplasms
Antigens, Differentiation
Immunosuppression
Apoptosis
Cell Proliferation
Immune Tolerance
Female
Male
Tumor Microenvironment
Biomarkers, Tumor
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Open Access location: http://cancerres.aacrjournals.org/content/early/2017/12/23/0008-5472.CAN-17-1833.full-text.pdf
Online Publication Date: 2017-12-26
Appears in Collections:Department of Immunology and Inflammation
Department of Metabolism, Digestion and Reproduction
Faculty of Medicine