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Usage Information

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.
View: Text | PDF | Corrigendum
Research Article Oncology Therapeutics

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

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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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Usage data is cumulative from June 2022 through June 2023.

Usage JCI PMC
Text version 1,001 197
PDF 108 65
Figure 281 4
Supplemental data 55 5
Citation downloads 52 0
Totals 1,497 271
Total Views 1,768
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Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.

Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.

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