Acute Myeloid Leukemia Promotes the Development and Function of Type 3 Innate Lymphoid Cells

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is not completely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity by secreting cytokines. Prior studies showed that AML blasts secrete aryl hydrocarbon receptor (AHR) ligands, and AHR is required for ILC3 development and function. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation. ILC3s in the setting of AML had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by TNFa. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo. These data support a model in which AML promotes ILC3 expansion and function to aid AML growth and survival. Overall design: BM from leukemic or WT transplanted mice were enriched for ILCs and progenitors by negative selection and sorted as Lin negative (CD3, CD14, CD19, Ter119, TCRß, Gr1, Fcer1a) CD45.1+ live cells. These cells were subjected to paired-end single cell RNA-sequencing using 10X Genomics Single Cell 3' v3.1 and libraries were sequenced using NovaSeq SP instrument.