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

Kaycee B. Moshofsky, Hyun J. Cho, Guanming Wu, Kyle A. Romine, Matthew T. Newman, Yoko Kosaka, Shannon K. McWeeney, Evan F. Lind

Research output: Contribution to journalArticle

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 CD81CD441 effector subpopulation and impaired activation of CD81CD62L1 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.

Original languageEnglish (US)
Pages (from-to)3038-3051
Number of pages14
JournalBlood Advances
Volume3
Issue number20
DOIs
StatePublished - Oct 22 2019

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T-Lymphocytes
Acute Myeloid Leukemia
Mitogen-Activated Protein Kinase Kinases
Programmed Cell Death 1 Ligand 2 Protein
Cell Death
Pharmaceutical Databases
Immune Evasion
trametinib
Gene Expression Profiling
Immunosuppressive Agents
Transcriptome
Immunotherapy
Cell Survival
Cell Proliferation
Ligands
Therapeutics
Population

ASJC Scopus subject areas

  • Hematology

Cite this

Moshofsky, K. B., Cho, H. J., Wu, G., Romine, K. A., Newman, M. T., Kosaka, Y., ... Lind, E. F. (2019). Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway. Blood Advances, 3(20), 3038-3051. https://doi.org/10.1182/bloodadvances.2019000574

Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway. / Moshofsky, Kaycee B.; Cho, Hyun J.; Wu, Guanming; Romine, Kyle A.; Newman, Matthew T.; Kosaka, Yoko; McWeeney, Shannon K.; Lind, Evan F.

In: Blood Advances, Vol. 3, No. 20, 22.10.2019, p. 3038-3051.

Research output: Contribution to journalArticle

Moshofsky, KB, Cho, HJ, Wu, G, Romine, KA, Newman, MT, Kosaka, Y, McWeeney, SK & Lind, EF 2019, 'Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway', Blood Advances, vol. 3, no. 20, pp. 3038-3051. https://doi.org/10.1182/bloodadvances.2019000574
Moshofsky, Kaycee B. ; Cho, Hyun J. ; Wu, Guanming ; Romine, Kyle A. ; Newman, Matthew T. ; Kosaka, Yoko ; McWeeney, Shannon K. ; Lind, Evan F. / Acute myeloid leukemia–induced T-cell suppression can be reversed by inhibition of the MAPK pathway. In: Blood Advances. 2019 ; Vol. 3, No. 20. pp. 3038-3051.
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