Format

Send to

Choose Destination
Cancer Cell. 2018 Apr 9;33(4):634-648.e5. doi: 10.1016/j.ccell.2018.02.007.

Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment.

Author information

1
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006 QLD, Australia.
2
Cancer Research Center of Toulouse, INSERM UMR 1037, 2 av Hubert Curien, 31037 Toulouse, France.
3
Institut Montpelliérain Alexander Grothendieck, CNRS, University Montpellier, 34095 Montpellier, France.
4
Cancer Research Center of Toulouse, INSERM UMR 1037, 2 av Hubert Curien, 31037 Toulouse, France; University Hospital, Dijon, 21000 Dijon, France.
5
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006 QLD, Australia; School of Medicine, University of Queensland, St Lucia 4006 QLD, Australia.
6
Immunology and Environment, LIMES Institute, University of Bonn, 53115 Bonn, Germany.
7
School of Medicine, University of Queensland, St Lucia 4006 QLD, Australia; Department of Bone Marrow Transplantation, QIMR Berghofer Medical Research Institute, Herston, 4006 QLD, Australia.
8
Department of Bone Marrow Transplantation, QIMR Berghofer Medical Research Institute, Herston, 4006 QLD, Australia.
9
Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
10
Mayo Clinic in Arizona, Phoenix, AZ 85054, USA.
11
Cancer Research Center of Toulouse, INSERM UMR 1037, 2 av Hubert Curien, 31037 Toulouse, France; Institut Universitaire du Cancer, Toulouse 31100, France.
12
Cancer Research Center of Toulouse, INSERM UMR 1037, 2 av Hubert Curien, 31037 Toulouse, France. Electronic address: ludovic.martinet@inserm.fr.
13
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, 4006 QLD, Australia; School of Medicine, University of Queensland, St Lucia 4006 QLD, Australia. Electronic address: mark.smyth@qimrberghofer.edu.au.

Abstract

Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from VkMYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses. Strikingly, high levels of bone marrow plasma IL-18 were associated with poor overall survival in MM patients. Furthermore, our preclinical studies suggested that IL-18 could be a potential therapeutic target in MM.

KEYWORDS:

IL-18; cancer; immunosuppression; immunotherapy; inflammasome; inflammation; myeloid-derived suppressor cells; myeloma; tumor microenvironment

PMID:
29551594
DOI:
10.1016/j.ccell.2018.02.007
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center