Verzella, D, Bennett, J, Fischietti, M et al. (17 more authors) (2018) GADD45β Loss Ablates Innate Immunosuppression in Cancer. Cancer Research, 78 (5). pp. 1275-1292. ISSN 0008-5472
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017, American Association for Cancer Research. This is an author produced version of a paper published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 08 Jan 2018 12:16 |
Last Modified: | 26 Dec 2018 01:38 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Identification Number: | 10.1158/0008-5472.CAN-17-1833 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125918 |