GADD45β loss ablates innate immunosuppression in cancer
File(s)
Supporting information
Accepted version
Author(s)
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.
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.
Date Issued
2018-03-01
Date Acceptance
2017-12-19
Citation
Cancer Research, 2018, 78 (5), pp.1275-1292
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
Medical Research Council (MRC)
Cancer Research UK
Bloodwise
Grant Number
MR/L005069/1
15115
15003
Subjects
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
Date Publish Online
2017-12-26