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

• Type of Material: Article
• Authors: Alisa B. Lee-Sherick, University of Colorado Anschutz Medical Campus; Kristen M. Jacobsen, University of Colorado Anschutz Medical Campus; Curtis Henry, Emory University; Madeline G. Huey, Emory University; Rebecca E. Parker, Emory University; Lauren S. Page, University of Colorado Anschutz Medical Campus; Amanda A. Hill, University of Colorado Anschutz Medical Campus; Xiaodong Wang, Eshelman School of Pharmacy; Stephen V. Frye, Eshelman School of Pharmacy; H. Shelton Earp, Lineberger Comprehensive Cancer Center, and.; Craig T. Jordan, University of Colorado; Deborah DeRyckere, Emory University; Doug Graham, Emory University
• Language: English
• Date: 2018-11-02
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2018, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.97941
• Title of Journal or Parent Work: JCI insight
• Volume: 3
• Issue: 21
• Grant/Funding Information: This work was supported by the NIH (5K12HD068372, to ABLS) (R01CA137078, to DKG), the Pablove Foundation, and Federal Funds from the National Cancer Institute NCI Experimental Therapeutics (NExT) program, NIH, contract no. HHSN261200800001E.
• Keywords: Oncology; Cancer immunotherapy; Therapeutics
• Research Categories: Health Sciences, Pharmacology; Biology, Microbiology; Health Sciences, Immunology

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.