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Blood Adv. 2019 Oct 22;3(20):3038-3051. doi: 10.1182/bloodadvances.2019000574.

Acute myeloid leukemia-induced T-cell suppression can be reversed by inhibition of the MAPK pathway.

Author information

1
School of Medicine.
2
Department of Molecular Microbiology & Immunology.
3
Division of Bioinformatics & Computational Biology, Department of Medical Informatics & Clinical Epidemiology.
4
Cancer Biology Graduate Program.
5
Knight Cancer Institute.
6
Oregon Clinical & Translational Research Institute, and.
7
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR.

Abstract

Acute myeloid leukemia (AML) remains difficult to treat due to mutational heterogeneity and the development of resistance to therapy. Targeted agents, such as MEK inhibitors, may be incorporated into treatment; however, the impact of MEK inhibitors on the immune microenvironment in AML is not well understood. A greater understanding of the implications of MEK inhibition on immune responses may lead to a greater understanding of immune evasion and more rational combinations with immunotherapies. This study describes the impact of trametinib on both T cells and AML blast cells by using an immunosuppressive mouse model of AML and primary patient samples. We also used a large AML database of functional drug screens to understand characteristics of trametinib-sensitive samples. In the mouse model, trametinib increased T-cell viability and restored T-cell proliferation. Importantly, we report greater proliferation in the CD8+CD44+ effector subpopulation and impaired activation of CD8+CD62L+ naive cells. Transcriptome analysis revealed that trametinib-sensitive samples have an inflammatory gene expression profile, and we also observed increased programmed cell death ligand 1 (PD-L1) expression on trametinib-sensitive samples. Finally, we found that trametinib consistently reduced PD-L1 and PD-L2 expression in a dose-dependent manner on the myeloid population. Altogether, our data present greater insight into the impact of trametinib on the immune microenvironment and characteristics of trametinib-sensitive patient samples.

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