Boosting antileukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ∼30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug repurposing screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS/ASXL1-driven (NA), MLL-rearranged, and NPM1-mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged survival. The survival benefits of TQ largely relied on T-cell functions. We showed that TQ synergized to downregulate immune checkpoint ligands and upregulate the STAT1- and CIITA-mediated expression of major histocompatibility complex class I (MHC-I) and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed the transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting the activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was consequently expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T-cell cocultures, TQ-treated T cells demonstrated greatly improved MHC-dependent killing of leukemia cells. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and antileukemia killing of endogenous T cells, leading to effective AML clearance.