Abstract 4729: The aryl hydrocarbon receptor directly regulates microRNA-29b to inhibit human natural killer cell development and function in acute myeloid leukemia
Authors: Scoville Steven D. , Nalin Ansel , Chen Luxi , Chen Li , McConnell Kathleen , Casas Susana Beceiro , Al-Rahman Abd , Hashi Naima , Zhang Michael , Saultz Jennifer , Yu Jianhua , Freud Aharon , Caligiuri Michael , Mundy-Bosse Bethany 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is a deadly disease in need of novel therapeutic avenues to improve outcomes. Natural killer (NK) cells have the potential to be curative in the setting of AML, although successful strategies to deploy NK cells in patients have been limited to date, likely due in part to cancer-derived immune suppression. Recently, we showed that NK cell development is impaired in the presence of AML. In our present study, we uncover a novel mechanism by which AML releases aryl hydrocarbon receptor (AHR) ligands that in turn activate the NK cells to induce expression of microRNA (miR)-29b, resulting in impaired NK cell development and function. This developmental block was dependent on miR-29b in NK cells, as miR-29b deficient NK cells were resistant to these changes in the presence of AML and miR-29b knockout mice engrafted with AML showed improved survival. In support of these findings in mice, AML patients with a transcriptional profile consistent with an activated AHR pathway had more aggressive disease and decreased survival (p=0.006). AML-derived AHR ligands impaired NK cell development by repressing Tbet and Eomes, two master regulators of late-stage NK cell maturation. We also show that agonist-bound AHR binds a dioxin-responsive element (DRE) located in the promoter of miR-29b to directly induce its transcription as demonstrated by luciferase constructs and anti-AHR ChIP-PCR in primary NK cells. Indeed, transwell co-cultures of AML and immature NK cells found increased miR-29b in NK cells and impaired development that was contact independent. These effects were reversed with addition of the AHR antagonist CH-223191. Finally, we show that AML cells pretreated with CH-223191 and then cultured with NK cells lead to more NK cell IFN-γ production and higher cytotoxicity against AML. Collectively, these data show that AML blasts secrete AHR ligands and AHR is a significant contributor to AML-induced immune suppression by upregulating miR-29b in NK cells and delaying their development, blunting their IFN-γ production and decreasing their cytotoxicity. Furthermore, we demonstrate that targeting AHR may be an effective novel therapeutic avenue because it promotes NK cell maturation while also enhancing NK cell-mediated activation and killing of AML cells.
Citation Format: Steven D. Scoville, Ansel Nalin, Luxi Chen, Li Chen, Kathleen McConnell, Susana Beceiro Casas, Abd Al-Rahman, Naima Hashi, Michael Zhang, Jennifer Saultz, Jianhua Yu, Aharon Freud, Michael Caligiuri, Bethany Mundy-Bosse. The aryl hydrocarbon receptor directly regulates microRNA-29b to inhibit human natural killer cell development and function in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4729.