Cancer Cell
Volume 33, Issue 4, 9 April 2018, Pages 634-648.e5
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Article
Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment

https://doi.org/10.1016/j.ccell.2018.02.007Get rights and content
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Highlights

  • IL-18 critically promotes MM progression through the generation of MDSCs

  • IL-18-driven MDSCs are key players in MM-associated immunosuppression

  • High BM IL-18 levels are associated with poor prognosis in MM patients

  • Dysregulated IL-18 might be a potential therapeutic target in MM

Summary

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

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

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These authors contributed equally

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