IL18 Promotes MDSC-Mediated Immunosuppression in Multiple Myeloma

Multiple myeloma is characterized by clonal expansion of bone marrow plasma cells, and it has been suggested that the bone marrow niche may represent a therapeutic target. The multiple myeloma microenvironment promotes tumor growth via dysregulated inflammation and mobilization of immunosuppressive myeloid-derived suppressor cells (MDSC), but the underlying mechanisms remain incompletely understood. Nakamura and colleagues found that the inflammatory cytokine IL18 is required for multiple myeloma progression in vivo. The NLRP1 inflammasome has been shown to produce IL18 in the context of obesity and metabolic syndrome and was also required for multiple myeloma progression. Accordingly, mice lacking IL18 and NLRP1 exhibited resistance to multiple myeloma, and this tumor resistance required CD8⁺ T cells. Mechanistically, IL18 promoted the function of MDSCs in the bone marrow niche in vivo, thereby suppressing antitumor effector T-cell activity to accelerate multiple myeloma progression. Global transcriptomic analysis was performed on CD138⁻ bone marrow aspirates from 73 patients with newly diagnosed multiple myeloma using RNA sequencing to comprehensively characterize the immune microenvironment. Polymorphonuclear (PMN)-MDSC signature genes were inversely correlated with cytotoxic lymphocyte signature genes, suggesting that PMN-MDSCs might limit cytotoxic T-cell activity in the multiple myeloma microenvironment in patients. Indeed, coculture experiments indicated that patient-derived bone marrow PMN-MDSCs suppressed the activity of patient-derived CD4⁺ and CD8⁺ T cells. Further, IL18 expression was correlated with expression of PMN-MDSC genes, and in a retrospective cohort of 152 patients with multiple myeloma, elevated IL18 in the bone marrow was associated with a poor prognosis. These findings suggest the potential for therapeutic targeting of IL18 in the multiple myeloma microenvironment, and, in vivo, an anti-IL18 antibody extended survival in combination with a proteasome inhibitor with known anti-myeloma efficacy. Collectively, these results elucidate a role for IL18 in generating an immunosuppressive bone marrow microenvironment to promote multiple myeloma progression.

Nakamura K, Kassem S, Cleynen A, Chrétien ML, Guillerey C, Putz EM, et al. Dysregulated IL-18 Is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer Cell 2018 Mar 15 [Epub ahead of print].

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