| First Author | Moshofsky KB | Year | 2019 |
| Journal | Blood Adv | Volume | 3 |
| Issue | 20 | Pages | 3038-3051 |
| PubMed ID | 31648326 | Mgi Jnum | J:360102 |
| Mgi Id | MGI:7797559 | Doi | 10.1182/bloodadvances.2019000574 |
| Citation | Moshofsky KB, et al. (2019) Acute myeloid leukemia-induced T-cell suppression can be reversed by inhibition of the MAPK pathway. Blood Adv 3(20):3038-3051 |
| abstractText | 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. |
