Group 1 Innate Lymphoid Cell Dysregulation in Acute Myeloid Leukemia

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a common and aggressive hematologic malignancy caused by a pathologic expansion of immature myeloid cells. Despite significant research efforts spanning 50 years, the 5-year survival rate in AML has remain relatively unchanged at <27.4%, underscoring the need for innovative approaches to treatment. Natural killer (NK) cells are a member of the group 1 innate lymphoid cell (ILC) family that play a pivotal role in the detection and elimination of leukemic cells. However, we and others have previously shown that AML is able to inhibit NK cell maturation, promoting disease progression. Mechanistically, we have shown that AML blasts are capable of secreting agonists for the aryl hydrocarbon receptor (AHR) transcription factor, which inhibits NK cell maturation and function. Accumulating evidence suggests that AHR is required for the maintenance of a related group 1 ILC subset termed an “ILC1.” Notably, ILC1s have been shown to be pro- tumorigenic in solid tumor mouse models. Therefore, we hypothesize that AML is able to skew ILC populations to suppress immune-surveillance by NK cells while promoting ILC1s. Preliminary data from our group support this hypothesis by demonstrating that AML is capable of expanding ILC1 populations in a tissue-specific manner in an AML mouse model. Furthermore, we predict that these ILC1s are functionally hyperactive in the setting of AML and promote disease progression. Our long-term goal in this project is to determine how AML leads to dysregulation of group 1 ILCs and to elucidate the downstream consequences on AML progression. Thus, our aims are 1) to identify and characterize the mechanism(s) which promote ILC1 expansion in AML and 2) to determine the functional consequences of expanded ILC1 populations in AML. To address these aims, we will use a combination of ex vivo and in vivo studies. First, we will determine whether AML promotes ILC1 expansion through interconversion from NK cells, skewing of ILC progenitors towards an ILC1 phenotype, and/or from direct proliferation of ILC1s. We will also use transgenic mouse models to assess the contribution of Ahr and ILC1- derived cytokines in promoting AML progression. By identifying these mechanisms, we will be able to better target these pathways to restore group 1 ILC homeostasis and inform the development of future immune-based therapies. This project represents a novel and innovative approach to targeted therapy in AML by focusing on how leukemia targets ILC populations, an area which has been understudied to date. Successful completion of these studies will fill in critical knowledge gaps of how ILCs are dysregulated in AML and how these cells can be targeted therapeutically to improve patient survival.