The Aryl Hydrocarbon Receptor is Associated with Monocytic AML and Innate Immune Resistance Reversible with an AHR inhibitor

Jennifer N Saultz^1*Daniel Bottomly¹Faith Burns¹Kaelan Byrd¹Yoko Kosaka¹Daniel Chandra¹Stephen Kurtz¹Guang Fan¹Andy Kaempf¹Marta Sanchez-Martin²Lei Wang²Karen McGovern²Dan S Kaufman³Shannon K McWeeney¹Brian J Druker¹Jeffrey Tyner¹Evan F Lind¹

• ¹Oregon Health and Science University, Portland, United States
• ²IKENA Oncology, Boston, MA 02210, United States
• ³University of California, San Diego, La Jolla, California, United States

This is a provisional file, not the final typeset article Acute myeloid leukemia (AML) is characterized by a complex interplay between genomic alterations, aberrant hematopoiesis, and immune evasion. The aryl hydrocarbon receptor (AHR) pathway is a critical player in this phenomenon determining the fate of stem cell differentiation as well as dictating immune cell development and function. Despite this critical connection, little is known about how AHR regulates the immune microenvironment in AML. Utilizing bulk RNA and single-cell RNA sequencing of AML patient samples, we found that AHR upregulation was associated with HLA-E expression on leukemic blasts and an innate immune resistant signature defined by upregulation of key cytokine pathways, interferon gamma (IFN-) pathway upregulation, MHC Class I/II and impaired NK cell profiles. High AHR expression in AML was associated with monocytic maturation and discrepant MHC class I/II profiles. Pre-treatment of leukemic blasts with an AHR inhibitor (AHRi) prior to NK cell killing assay downregulated key checkpoint molecules including HLA-E, key interferon gamma signaling transcription factors (STAT1, IRF1) and led to enhanced NK cell killing among multiple FAB subsets in AML. The data support targeting the AHR pathway as a dual tumor intrinsic and immune targeting therapeutic strategy for AML, particularly in combination with NK cellular therapy.