MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity
Alisa B. Lee-Sherick, … , Deborah DeRyckere, Douglas K. Graham
Alisa B. Lee-Sherick, … , Deborah DeRyckere, Douglas K. Graham
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e97941. https://doi.org/10.1172/jci.insight.97941.
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Categories: Research Article Oncology Therapeutics

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

Abstract

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.

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

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Figure 1

MERTK inhibitor MRX-2843 decreases leukemic burden and increases survival in an orthotopic ALL xenograft model.

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MERTK inhibitor MRX-2843 decreases leukemic burden and increases surviva...
697 B-ALL cells expressing the firefly luciferase gene were inoculated into NSG mice by tail vein injection. Disease burden was assessed by bioluminescence imaging, and survival was monitored. (A–D) Mice were treated with 50 mg/kg (dashed green line) or 75 mg/kg (solid green line) MERTK inhibitor MRX-2843 or an equivalent volume of vehicle (saline; solid black line) once daily, beginning 1 day after leukemia cell injection to model low leukemic burden. (B) Representative bioluminescence images. (C) Mean bioluminescence intensities and SEM (n = 10–11, *P < 0.05, **P < 0.01, ****P < 0.0001, ‡P < 0.05, ‡‡‡‡P <0.0001; 1-way ANOVA; *comparison between saline and 75 mg/kg UNC2025); ‡comparison between saline and 50 mg/kg UNC2025. (D) Kaplan-Meier survival curves (n = 7–10, P < 0.0001 compared with vehicle, log-rank test). (E–H) Leukemic mice were randomized to groups with equal mean bioluminescence intensities and treated with 75 mg/kg MRX-2843 or an equivalent volume of vehicle (saline) daily, beginning 12 days after tumor inoculation to model existent disease. (F) Representative bioluminescence images. (G) Mean bioluminescence intensities and standard errors (n = 10). (H) Kaplan-Meier survival curves (n = 10, P < 0.0001 compared with vehicle, log-rank test). Data shown are representative of 2 independent experiments.