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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: 26-Dec-2017
Date of Acceptance: 11-Dec-2017
URI: http://hdl.handle.net/10044/1/55461
DOI: https://dx.doi.org/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
Leukaemia & Lymphoma Research "Beating Blood Cancers"
Funder's Grant Number: MR/L005069/1
15115
15003
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
NF-KAPPA-B
TUMOR-ASSOCIATED MACROPHAGES
HEPATOCELLULAR-CARCINOMA
CHEMICAL HEPATOCARCINOGENESIS
INFILTRATING MACROPHAGES
LYMPHOID STRUCTURES
INFLAMMATION
PROGRESSION
ACTIVATION
IMMUNITY
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
Appears in Collections:Division of Surgery
Department of Medicine
Faculty of Medicine



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