Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC.

Authors

Meher Bolisetti Gayatri, Bei Jia, Anthony J Veltri, Vysakh Anandan, Maoshuo Yang, Jing Li, Kenneth Man Hei Chan, Sophie Verbeke, Jiangchen Yao, Sarah E Granozio, Yun Jiang, Esra'a Keewan, Jacqueline Ann Cook, Xiaolan Zhu, Erik A Ranheim, Zhe Wang, Chih-Hsing Chou, Kalyan V Nadiminti, H Leighton Grimes, Marulasiddappa Suresh, Hong Zheng, Xiaona You, Jing Zhang

Published in

Blood. Aug 04, 2026. Epub Aug 04, 2026.

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 re-purpose 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-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus 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 co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.

PMID:
42550775
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.

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