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

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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. Nakamura et al. show that IL-18 produced by the multiple myeloma (MM) niche promotes MM progression in a CD8 + T cell-dependent manner in a mouse model and that IL-18 could be a potential therapeutic target in MM. High levels of bone marrow plasma IL-18 are associated with poor overall survival in MM patients.

Original languageEnglish (US)
Pages (from-to)634-648.e5
JournalCancer cell
Volume33
Issue number4
DOIs
StatePublished - Apr 9 2018

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment'. Together they form a unique fingerprint.

Cite this