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

Kyohei Nakamura; Sahar Kassem; Alice Cleynen; Marie-Lorraine Chrétien; Camille Guillerey; Eva Maria Putz; Tobias Bald; Irmgard Förster; Slavica Vuckovic; Geoffrey R Hill; Seth L Masters; Marta Chesi; P Leif Bergsagel; Hervé Avet-Loiseau; Ludovic Martinet; Mark J Smyth

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

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

Authors

Kyohei Nakamura¹, Sahar Kassem², Alice Cleynen³, Marie-Lorraine Chrétien⁴, Camille Guillerey⁵, Eva Maria Putz¹, Tobias Bald¹, Irmgard Förster⁶, Slavica Vuckovic⁷, Geoffrey R Hill⁸, Seth L Masters⁹, Marta Chesi¹⁰, P Leif Bergsagel¹⁰, Hervé Avet-Loiseau¹¹, Ludovic Martinet¹², Mark J Smyth¹³

Affiliations

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.

PMID: 29551594
DOI: 10.1016/j.ccell.2018.02.007

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 Vk^∗MYC 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Immune Tolerance
Interleukin-18 / blood
Interleukin-18 / metabolism*
Male
Mice
Multiple Myeloma / genetics
Multiple Myeloma / immunology
Multiple Myeloma / pathology*
Myeloid-Derived Suppressor Cells / immunology*
Myeloid-Derived Suppressor Cells / pathology
Neoplasm Transplantation
Prognosis
Proto-Oncogene Proteins c-myc / genetics
Survival Analysis
Tumor Microenvironment
Up-Regulation*

Substances

IL18 protein, human
Interleukin-18
MYC protein, human
Proto-Oncogene Proteins c-myc