MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity

• DOI: 10.1172/jci.insight.97941
• Publication Date: 2018-10-23T21:12:57Z
• Authors: Alisa B. Lee-Sherick; Kristen M. Jacobsen; Curtis J. Henry; Madeline G. Huey; Rebecca E. Parker; Lauren S. Page; Amanda A. Hill; Xiaodong Wang; Stephen V. Frye; H. Shelton Earp; Craig T. Jordan; Deborah DeRyckere; Douglas K. Graham
• Keywords: MERTK

MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells thus a potential therapeutic target. Here we demonstrate both direct effects of inhibition on induction anti-leukemia immunity via suppression the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated immunocompromised mice bearing MERTK-expressing human xenograft. In addition, host by genetic deletion (Mertk-/- mice) or treatment with MRX-2843 significantly decreased tumor burden prolonged immune-competent inoculated MERTK-negative ALL, suggesting immune-mediated activity. this context, led to significant decreases expression ligands PD-L1 PD-L2 CD11b+ monocytes/macrophages microenvironment. Furthermore, although T do not express MERTK, indirectly CD4+ CD8+ incidence splenic FOXP3+ Tregs at sites leukemic infiltration, leading increased cell activation. These data activities response ALL models provide validation translational agent targeting for modulation immunity.