Innate lymphoid cells (ILCs) have emerged as a new family of innate immune cells implicated in the regulation of diverse processes, including resistance to pathogens, autoimmune inflammation, and tissue homeostasis. 1 ILCs lack rearranged antigen receptors and reside predominantly in tissues wherein they express cytokines in response to signals in the tissue microenvironment. Three distinct human ILC subsets have been described on the basis of their cytokine profile and transcriptional regulation which mirror well-characterized T-helper cell subsets: T-bet+ ILC1 secretes interferon-γ (IFN-γ), GATA3+ ILC2 secretes interleukin-4 (IL-4)/IL-5/IL-13, and Rorγt+ ILC3 secretes IL-17 and IL-22. 2 Recent studies have examined pro-or antitumor properties of ILC subsets in mouse models. 3, 4, 5 Changes in circulating ILC subsets in human leukemia have been described, 6, 7 but data relating to changes in ILC subsets in the tumor microenvironment in human preneoplastic states are lacking.

All cases of multiple myeloma (MM) are preceded by precursor monoclonal gammopathy of undetermined significance (MGUS). 8 Prior studies have shown the capacity of the immune system to recognize these earliest lesions, which correlate with reduced risk of progression to clinical malignancy. 9, 10, 11 Immunomodulatory drugs (IMiDs) such as lenalidomide or pomalidomide form a component of standard MM therapy and have shown promising activity for prevention of malignancy. 12 IMiDs are thought to act in part by inducing cereblon-mediated degradation of Ikzf1 and Ikzf3. 13 IMiD-mediated T-cell/NK T-cell (T/NKT) activation depends on antigen-mediated stimulation. 14, 15 However, the spectrum of potential cellular targets of IMiDs still remains to be fully characterized. Recent findings that human ILC1 subsets express high levels of Ikzf3 16 raised the possibility that ILCs may also be targets of IMiD-mediated immune regulation. Tumor cells in MGUS/MM reside primarily in the bone marrow. However, data relating to functional characterization of human ILC subsets in the normal marrow and in the setting of plasma cell disorders are lacking. These considerations led us to explore changes in ILC subsets in blood and bone marrow of patients with MGUS/MM and after IMiD therapy.