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

Publication date: 9 April 2018
Source:Cancer Cell, Volume 33, Issue 4
Author(s): 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
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.

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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.


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