MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity
MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity
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DOI：
10.1172/jci.insight.97941
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发表时间：
2018-11-02
期刊：
影响因子：
8
通讯作者：
Graham, Douglas K.
中科院分区：
文献类型：
--
作者：
Lee-Sherick, Alisa B.;Jacobsen, Kristen M.;Graham, Douglas K.
MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk(-/)-mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b(+) monocytes/macrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4(+) and CD8(+) T cells and decreased the incidence of splenic FOXP3(+) Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity.
